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RAP1A; RAP1A, member of RAS oncogene family (1p13.3)

Gene Summary

Gene:RAP1A; RAP1A, member of RAS oncogene family
Aliases: RAP1, C21KG, G-22K, KREV1, KREV-1, SMGP21
Location:1p13.3
Summary:This gene encodes a member of the Ras family of small GTPases. The encoded protein undergoes a change in conformational state and activity, depending on whether it is bound to GTP or GDP. This protein is activated by several types of guanine nucleotide exchange factors (GEFs), and inactivated by two groups of GTPase-activating proteins (GAPs). The activation status of the encoded protein is therefore affected by the balance of intracellular levels of GEFs and GAPs. The encoded protein regulates signaling pathways that affect cell proliferation and adhesion, and may play a role in tumor malignancy. Pseudogenes of this gene have been defined on chromosomes 14 and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]
Databases:OMIM, HGNC, GeneCard, Gene
Protein:ras-related protein Rap-1A
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (19)

Pathways:

What pathways are this gene/protein implicaed in?
- Integrin Signaling Pathway BIOCARTA
- Signaling of Hepatocyte Growth Factor Receptor BIOCARTA
- Focal adhesion KEGG
- Leukocyte transendothelial migration KEGG
- Long-term potentiation KEGG
- MAPK signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • GTP-Binding Proteins
  • Protein Isoforms
  • Breast Cancer
  • Cancer Gene Expression Regulation
  • Recombinant Fusion Proteins
  • Messenger RNA
  • Proto-Oncogene Proteins
  • rap GTP-Binding Proteins
  • ras Proteins
  • siRNA
  • RAP1A
  • Gene Expression Profiling
  • Cell Proliferation
  • RNA Splicing
  • Signal Transduction
  • Thyroid Cancer
  • Proteins
  • Mutation
  • Tumor Markers
  • Base Sequence
  • Lung Cancer
  • Two-Hybrid System Techniques
  • Protein Binding
  • Chromosome 1
  • Amino Acid Sequence
  • RTPCR
  • DNA Mutational Analysis
  • Microtubule-Associated Proteins
  • rac GTP-Binding Proteins
  • DNA Primers
  • RHOA
  • Western Blotting
  • Molecular Sequence Data
  • Hemangioma, Cavernous, Central Nervous System
  • Twist Transcription Factor
  • GTPase-Activating Proteins
  • rap1 GTP-Binding Proteins
  • Sequence Homology
  • Pedigree
  • Adenocarcinoma
  • Renin
  • ras GTPase-Activating Proteins
Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (3)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Lung CancerLung Cancer and RAP1A View Publications22
Breast CancerBreast Cancer and RAP1A View Publications20
Thyroid CancerThyroid Cancer and RAP1A View Publications13

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: RAP1A (cancer-related)

Sayyah J, Bartakova A, Nogal N, et al.
The Ras-related protein, Rap1A, mediates thrombin-stimulated, integrin-dependent glioblastoma cell proliferation and tumor growth.
J Biol Chem. 2014; 289(25):17689-98 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
Rap1 is a Ras family GTPase with a well documented role in ERK/MAP kinase signaling and integrin activation. Stimulation of the G-protein-coupled receptor PAR-1 with thrombin in human 1321N1 glioblastoma cells led to a robust increase in Rap1 activation. This response was sustained for up to 6 h and mediated through RhoA and phospholipase D (PLD). Thrombin treatment also induced a 5-fold increase in cell adhesion to fibronectin, which was blocked by down-regulating PLD or Rap1A or by treatment with a β1 integrin neutralizing antibody. In addition, thrombin treatment led to increases in phospho-focal adhesion kinase (tyrosine 397), ERK1/2 phosphorylation and cell proliferation, which were significantly inhibited in cells treated with β1 integrin antibody or Rap1A siRNA. To assess the role of Rap1A in tumor formation in vivo, we compared growth of 1321N1 cells stably expressing control, Rap1A or Rap1B shRNA in a mouse xenograft model. Deletion of Rap1A, but not of Rap1B, reduced tumor mass by >70% relative to control. Similar observations were made with U373MG glioblastoma cells in which Rap1A was down-regulated. Collectively, these findings implicate a Rap1A/β1 integrin pathway, activated downstream of G-protein-coupled receptor stimulation and RhoA, in glioblastoma cell proliferation. Moreover, our data demonstrate a critical role for Rap1A in glioblastoma tumor growth in vivo.

Related: ITGB1 RHOA


Qiang W, Wu Q, Zhou F, et al.
Suppression of telomere-binding protein TPP1 resulted in telomere dysfunction and enhanced radiation sensitivity in telomerase-negative osteosarcoma cell line.
Biochem Biophys Res Commun. 2014; 445(2):363-8 [PubMed] Related Publications
Mammalian telomeres are protected by the shelterin complex that contains the six core proteins POT1, TPP1, TIN2, TRF1, TRF2 and RAP1. TPP1, formerly known as TINT1, PTOP, and PIP1, is a key factor that regulates telomerase recruitment and activity. In addition to this, TPP1 is required to mediate the shelterin assembly and stabilize telomere. Previous work has found that TPP1 expression was elevated in radioresistant cells and that overexpression of TPP1 led to radioresistance and telomere lengthening in telomerase-positive cells. However, the exact effects and mechanism of TPP1 on radiosensitivity are yet to be precisely defined in the ALT cells. Here we report on the phenotypes of the conditional deletion of TPP1 from the human osteosarcoma U2OS cells using ALT pathway to extend the telomeres.TPP1 deletion resulted in telomere shortening, increased apoptosis and radiation sensitivity enhancement. Together, our findings show that TPP1 plays a vital role in telomere maintenance and protection and establish an intimate relationship between TPP1, telomere and cellular response to ionizing radiation, but likely has the specific mechanism yet to be defined.

Related: Apoptosis Osteosarcoma


Vitali E, Peverelli E, Giardino E, et al.
Cyclic adenosine 3'-5'-monophosphate (cAMP) exerts proliferative and anti-proliferative effects in pituitary cells of different types by activating both cAMP-dependent protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac).
Mol Cell Endocrinol. 2014; 383(1-2):193-202 [PubMed] Related Publications
In the pituitary the activation of cyclic adenosine 3'-5'-monophosphate (cAMP) dependent pathways generates proliferative signals in somatotrophs, whereas in pituitary cells of other lineages its effect remains uncertain. Moreover, the specific role of the two main cAMP effectors, protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac), has not been defined. Aim of this study was to investigate the effect of cAMP on pituitary adenomatous cells proliferation and to identify PKA and Epac differential involvement. We found that cAMP increased DNA synthesis and cyclin D1 expression in somatotropinomas, whereas it reduced both parameters in prolactinomas and nonfunctioning adenomas, these effects being replicated in corresponding cell lines. Moreover, the divergent cAMP effects were mimicked by Epac and PKA analogs, which activated Rap1 and CREB, respectively. In conclusion, we demonstrated that cAMP exerted opposite effects on different pituitary cell types proliferation, these effects being mediated by both Epac and PKA.

Related: Pituitary Tumors Signal Transduction


Pradhan MP, Desai A, Palakal MJ
Systems biology approach to stage-wise characterization of epigenetic genes in lung adenocarcinoma.
BMC Syst Biol. 2013; 7:141 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
BACKGROUND: Epigenetics refers to the reversible functional modifications of the genome that do not correlate to changes in the DNA sequence. The aim of this study is to understand DNA methylation patterns across different stages of lung adenocarcinoma (LUAD).
RESULTS: Our study identified 72, 93 and 170 significant DNA methylated genes in Stages I, II and III respectively. A set of common 34 significant DNA methylated genes located in the promoter section of the true CpG islands were found across stages, and these were: HOX genes, FOXG1, GRIK3, HAND2, PRKCB, etc. Of the total significant DNA methylated genes, 65 correlated with transcription function. The epigenetic analysis identified the following novel genes across all stages: PTGDR, TLX3, and POU4F2. The stage-wise analysis observed the appearance of NEUROG1 gene in Stage I and its re-appearance in Stage III. The analysis showed similar epigenetic pattern across Stage I and Stage III. Pathway analysis revealed important signaling and metabolic pathways of LUAD to correlate with epigenetics. Epigenetic subnetwork analysis identified a set of seven conserved genes across all stages: UBC, KRAS, PIK3CA, PIK3R3, RAF1, BRAF, and RAP1A. A detailed literature analysis elucidated epigenetic genes like FOXG1, HLA-G, and NKX6-2 to be known as prognostic targets.
CONCLUSION: Integrating epigenetic information for genes with expression data can be useful for comprehending in-depth disease mechanism and for the ultimate goal of better target identification.

Related: Lung Cancer


Onodera Y, Nam JM, Bissell MJ
Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways.
J Clin Invest. 2014; 124(1):367-84 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
There is a considerable resurgence of interest in the role of aerobic glycolysis in cancer; however, increased glycolysis is frequently viewed as a consequence of oncogenic events that drive malignant cell growth and survival. Here we provide evidence that increased glycolytic activation itself can be an oncogenic event in a physiologically relevant 3D culture model. Overexpression of glucose transporter type 3 (GLUT3) in nonmalignant human breast cells activated known oncogenic signaling pathways, including EGFR, β1 integrin, MEK, and AKT, leading to loss of tissue polarity and increased growth. Conversely, reduction of glucose uptake in malignant cells promoted the formation of organized and growth-arrested structures with basal polarity, and suppressed oncogenic pathways. Unexpectedly and importantly, we found that unlike reported literature, in 3D the differences between "normal" and malignant phenotypes could not be explained by HIF-1α/2α, AMPK, or mTOR pathways. Loss of epithelial integrity involved activation of RAP1 via exchange protein directly activated by cAMP (EPAC), involving also O-linked N-acetylglucosamine modification downstream of the hexosamine biosynthetic pathway. The former, in turn, was mediated by pyruvate kinase M2 (PKM2) interaction with soluble adenylyl cyclase. Our findings show that increased glucose uptake activates known oncogenic pathways to induce malignant phenotype, and provide possible targets for diagnosis and therapeutics.

Related: ITGB1 Breast Cancer SLC2A3 AKT1 EGFR


Panero J, Stanganelli C, Arbelbide J, et al.
Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression.
Blood Cells Mol Dis. 2014 Feb-Mar; 52(2-3):134-9 [PubMed] Related Publications
The core complex of telomere-associated proteins, named the shelterin complex, plays a critical role in telomere protection and telomere length (TL) homeostasis. In this study, we have explored changes in the expression of telomere-associated genes POT1, TIN2, RAP1 and TPP1, in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). A total of 154 patients: 70 with MGUS and 84 with MM were studied. Real-time quantitative PCR was used to quantify gene expression. TL was evaluated by Terminal Restriction Fragments. Our data showed increased expression of POT1, TPP1, TIN2 and RAP1 in MM with respect to MGUS patients, with significant differences for POT1 gene (p=0.002). In MM, the correlation of gene expression profiles with clinical characteristics highlighted POT1 for its significant association with advanced clinical stages, high calcium and β2-microglobulin levels (p=0.02) and bone lesions (p=0.009). In multivariate analysis, POT1 expression (p=0.04) was a significant independent prognostic factor for overall survival as well as the staging system (ISS) (p<0.02). Our findings suggest for the first time the participation of POT1 in the transformation process from MGUS to MM, and provide evidence of this gene as a useful prognostic factor in MM as well as a possible molecular target to design new therapeutic strategies.

Related: Myeloma Myeloma - Molecular Biology POT1


El Idrissi M, Hervieu V, Merle P, et al.
Cause-specific telomere factors deregulation in hepatocellular carcinoma.
J Exp Clin Cancer Res. 2013; 32:64 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
BACKGROUND: Among the numerous genetic defects associated with hepatocarcinogenesis, telomere abnormalities appear to play a role both in tumor promotion and maintenance. Telomeres, the chromosome extremities, are protected by specific proteins, the shelterin complex and by additional factors. Besides telomerase dysregulation, expression changes of these telomere factors have been observed in cancers.
METHODS: Here, we tested the hypothesis that such dysregulation might occur in hepatocellular carcinoma (HCC) with specific patterns depending on the cause of HCC. We compared telomere length, telomerase activity (TA), hTERT and telomere genes expression using PCR and Western-blot analyses between non-cirrhotic liver, peritumoral cirrhotic tissue (40 samples) and cancerous tissue (40 samples) derived from 40 patients with HBV-, HCV-, or alcohol-related HCC.
RESULTS: Alterations in TA, hTERT expression and telomere length between non-cirrhotic, cirrhotic, and tumor samples were not significantly influenced by the cause of HCC. In contrast, the expression pattern of hTR, shelterin, and non-shelterin telomere protective factors clearly distinguished the 3 causes of cirrhosis and HCC. For patients with HBV diseased liver, when compared with non-cirrhotic liver, the cirrhotic tissue underexpressed all shelterin and all but HMRE11A and RAD50 non-shelterin telomere factors. For HCV the expression level of POT1, RAP1, Ku80, and RAD50 was higher in cirrhotic than in non-cirrhotic liver samples without evidence for significant transcriptional change for the remaining genes. For alcohol-related liver diseases, the expression level of POT1, RAP1, TIN2, hMRE11A, hMRE11B, Ku70, Ku80, RAD50, TANK1, and PINX1 was higher in cirrhotic than in non-cirrhotic liver samples. For the 3 causes of HCC, there was no significant change in shelterin and non-shelterin gene expression between cirrhosis and HCC samples.
CONCLUSIONS: These results validate our hypotheses and demonstrate that cirrhosis and HCC add-up numerous telomere dysfunctions including numerous cause-specific changes that appear to occur early during the course of the disease.

Related: Liver Cancer TERC


Sakai NS, Samia-Aly E, Barbera M, Fitzgerald RC
A review of the current understanding and clinical utility of miRNAs in esophageal cancer.
Semin Cancer Biol. 2013; 23(6 Pt B):512-21 [PubMed] Related Publications
BACKGROUND: MicroRNAs (miRNAs) are a class of small, well-conserved, non-coding RNAs that regulate the translation of RNAs. They have a role in biological and pathological process including cell differentiation, apoptosis, proliferation and metabolism. Since their discovery, they have been shown to have a potential role in cancer pathogenesis through their function as oncogenes or tumor suppressors. A substantial number of miRNAs show differential expression in esophageal cancer tissues, and so have been investigated for possible use in diagnosis. Furthermore, there is increasing interest in their use as prognostic markers and determining treatment response, as well as identifying their downstream targets and understanding their mode of action.
METHODS: We analyzed the most recent studies on miRNAs in esophageal cancer and/or Barrett's esophagus (BE). The publications were identified by searching in PuBMed for the following terms: Barrett's esophagus and microRNA; esophageal cancer and microRNA.
RESULTS: Four miRNAs (mi-R-25, -99a, -133a and -133b) showed good potential as diagnostic markers and interestingly five (mi-R-21, -27b, -126, - 143 and -145) appeared to be useful both as diagnostic and prognostic/predictive markers.
CONCLUSION: The data so far on miRNAs in esophageal carcinogenesis is promising but further work is required to determine whether miRNAs can be used as biomarkers, not only in the clinical setting or added to individualized treatment regimes but also in non-invasive test by making use of miRNAs identified in blood.

Related: Cancer of the Esophagus Esophageal Cancer


Dadkhah E, Naseh H, Farshchian M, et al.
A cancer-array approach elucidates the immune escape mechanism and defects in the DNA repair system in esophageal squamous cell carcinoma.
Arch Iran Med. 2013; 16(8):463-70 [PubMed] Related Publications
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the second-most frequently diagnosed cancer in Northeast Iran, often diagnosed in advanced stages. No standard early diagnostic guideline has been proposed to date and current therapeutic modalities are not effective. Detection of tumor-specific biomarkers, which is the goal of this study, could prove useful in the diagnosis of ESCC. 
METHODS: To better understand the gene expression profile of ESCC, we analyzed tumor samples and corresponding adjacent normal tissues from ESCC patients by Chemiluminescent Human Cancer GEArrays. Candidate genes were verified by real-time PCR. 
RESULTS: Out of 440 cancer-related genes included in the array, 71 were overexpressed compared to normal tissue, with significant differences in 11 genes. There were 108 genes underexpressed, with significant differences in 5 genes. Until now, the AP2M1, FTL, UBE2L6, HLA-C, and HSPA8 overexpressed genes and XRCC5, TP53I3 and RAP1A underexpressed genes were not reported in ESCC. We chose the MMP2, HLA-G, and XRCC5 markers from 58 Iranian ESCC patients to verify the expression validity by real-time PCR. The microarray results were confirmed with two-tailed significance levels of P = 0.003 (MMP2), P = 0.000 (HLA-G) and P = 0.002(XRCC5). Analysis performed for the candidate genes using GNCpro online software highlighted two pathways, an immuno-modulatory response and DNA replication and repair. We successfully performed and validated Chemiluminescent GEArray gene expression profiling in ESCC. Several biomarkers that might be related to tumorigenesis in ESCC were identified.
CONCLUSION: Immuno-modulatory and DNA repair pathways could be used as targets to locate specific diagnostic, prognostic, and therapeutic biomarkers for ESCC.

Related: Cancer of the Esophagus Esophageal Cancer


Orso F, Balzac F, Marino M, et al.
miR-21 coordinates tumor growth and modulates KRIT1 levels.
Biochem Biophys Res Commun. 2013; 438(1):90-6 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
miR-21 is overexpressed in tumors and it displays oncogenic activity. Here, we show that expression of miR-21 in primary tumors anticorrelates with KRIT1/CCM1, an interacting partner of the Ras-like GTPase Rap1, involved in Cerebral Cavernous Malformations (CCM). We present evidences that miR-21 silences KRIT1 by targeting its mRNA 3'UTR and that this interaction is involved in tumor growth control. In fact, miR-21 over-expression or KRIT1 knock-down promote anchorage independent tumor cell growth compared to controls, whereas the opposite is observed when anti-miR-21 or KRIT1 overexpression are employed. Our findings suggest that miR-21 promotes tumor cell growth, at least in part, by down-modulating the potential tumor suppressor KRIT1.

Related: Breast Cancer miR-21


Grippaudo FR, Piane M, Amoroso M, et al.
Cutaneous venous malformations related to KRIT1 mutation: case report and literature review.
J Mol Neurosci. 2013; 51(2):442-5 [PubMed] Related Publications
Cavernous malformations (CMs) are vascular anomalies of the nervous system mostly located in the brain. Cerebral cavernous malformations can present sporadically or familial, as a consequence of an autosomal dominant condition, with incomplete penetrance and variable clinical expression. Occasionally, extraneural manifestations of CMs involving the skin have been described. We report the case of two siblings presenting in adulthood diffuse cutaneous vascular lesions associated with cerebral CMs that, after surgical excision and histopathologic analysis, resulted to cavernous haemangiomas. Genomic DNA was extracted from peripheral blood, and molecular evaluation of KRIT1 gene was performed. Although no signs of neurological impairment were reported, cerebral MRI revealed multiple images in both patients, suggestive of cavernous haemangiomas. The genetic study demonstrated a nonsense mutation (c.535C>T) in the KRIT1 (Krev-1/rap1 interaction trapped 1) gene. Few reports describe extraneural manifestations of Cavernous malformation syndrome (CMs) related to a KRIT1 mutation; these involve the skin and are associated with hyperkeratotic cutaneous capillary-venous malformation. CMs should be suspected in patients developing multiple nodular cutaneous venous lesions in adulthood.

Related: Brain and Spinal Cord Tumours


Minato N
Rap G protein signal in normal and disordered lymphohematopoiesis.
Exp Cell Res. 2013; 319(15):2323-8 [PubMed] Related Publications
Rap proteins (Rap1, Rap2a, b, c) are small molecular weight GTPases of the Ras family. Rap G proteins mediate diverse cellular events such as cell adhesion, proliferation, and gene activation through various signaling pathways. Activation of Rap signal is regulated tightly by several specific regulatory proteins including guanine nucleotide exchange factors and GTPase-activating proteins. Beyond cell biological studies, increasing attempts have been made in the past decade to define the roles of Rap signal in specific functions of normal tissue systems as well as in cancer. In the immune and hematopoietic systems, Rap signal plays crucial roles in the development and function of essentially all lineages of lymphocytes and hematopoietic cells, and importantly, deregulated Rap signal may lead to unique pathological conditions depending on the affected cell types, including various types of leukemia and autoimmunity. The phenotypical studies have unveiled novel, even unexpected functional aspects of Rap signal in cells from a variety of tissues, providing potentially important clues for controlling human diseases, including malignancy.

Related: Leukemia Signal Transduction


Elsabah MT, Adel I
Immunohistochemical assay for detection of K-ras protein expression in metastatic colorectal cancer.
J Egypt Natl Canc Inst. 2013; 25(1):51-6 [PubMed] Related Publications
BACKGROUND: The monoclonal antibodies (mAbs) that target the epidermal growth factor receptor (EGFR) had expanded the range of treatment options for metastatic colorectal cancer. However, such type of treatment was shown to be ineffective if there is K-ras mutation. In most previous studies K-ras gene mutation was mainly assessed by PCR.
AIM: Our work is designed to detect K-ras protein expression by immunohistochemistry (IHC) aiming to reach a preliminary method that could be confirmed by PCR and considered an alternative way for the detection of K-ras aberration. We are also aiming to find a relation between K-ras protein expression and K-ras gene mutation.
MATERIALS AND METHODS: Paraffin embedded tissue samples from 26 metastatic colorectal cancer (mCRC) patients were analyzed for K-ras protein expression by IHC using Rap1A polyclonal antibody. Staining patterns were subjectively assessed and correlated with clinicopathological features. The results were statistically evaluated using the Chi-square test.
RESULTS: K-ras cytoplasmic positivity was observed in 42.3% of cases. The positivity was either strong in 26.9% or moderate in 15.4%. With respect to adenocarcinoma variants, 50% of cases were positive for K-ras protein expression while all mucinous and signet ring types were negative. The positivity was noted in 50% of moderately differentiated GII colorectal carcinomas as compared with 38.9% in poorly differentiated GIII. Positive staining was observed in 40% of cases with positive lymph node metastasis while in the absence of nodal metastasis the positivity was 45.5%. No significant correlation was found between clinicopathological parameters and K-ras staining results.
CONCLUSION: IHC may compliment PCR in the detection of K-ras mutation.

Related: Colorectal (Bowel) Cancer KRAS gene


Spina A, Sorvillo L, Esposito A, et al.
Inorganic phosphate as a signaling molecule: a potential strategy in osteosarcoma treatment.
Curr Pharm Des. 2013; 19(30):5394-403 [PubMed] Related Publications
Inorganic phosphate (Pi) is an essential nutrient to living organisms. It plays a key role in diverse biological processes, including osteoblast differentiation and skeletal mineralization. Maintenance of proper Pi homeostasis is a critical event, as any deviation from that state can lead to several acute and chronic disease states and influence the ageing process and lifespan. Serum Pi level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, renal tubular reabsorption and depends mainly on the activity of Na/Pi cotransporters. Pi is abundant in the diet and intestinal absorption of Pi is efficient and minimally regulated. The kidney is a major regulator of Pi homeostasis and can increase or decrease its Pi reabsorptive capacity to accommodate Pi need. Relevantly, Pi is emerging as an important signalling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression and protein abundance in many cell types. However, little is known about the initial events involving the detection of changes in serum or local Pi concentrations and the subsequent downstream regulation cascade. Previously, we provided evidence that Pi inhibits proliferation and aggressiveness of human osteosarcoma U2OS cells identifying adenylate cyclase, beta3 integrin, Rap1, ERK1/2 as proteins whose expression and function are relevantly affected in response to Pi. More recently, we demonstrated that Pi is capable also of inducing sensitization of osteosarcoma cells to doxorubicin in a p53-dependent manner and through a mechanism involving ERK1/2 down-regulation. This review summarizes the current knowledge regarding inorganic phosphate as a novel specific signaling molecule in bone and other cell types in mammals and discuss how targeting Pi levels at local sites might represent a potential strategy for improving osteosarcoma therapy.

Related: Osteosarcoma


Van Tubergen EA, Banerjee R, Liu M, et al.
Inactivation or loss of TTP promotes invasion in head and neck cancer via transcript stabilization and secretion of MMP9, MMP2, and IL-6.
Clin Cancer Res. 2013; 19(5):1169-79 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
PURPOSE: Invasion is the critical step in progression of a precancerous lesion to squamous cell carcinoma of the head and neck (HNSCC). Invasion is regulated by multiple proinflammatory mediators. Tristetraprolin (TTP) is an mRNA-degrading protein that regulates multiple proinflammatory mediators. TTP may serve as an excellent treatment target. Rap1 is a ras-like oncoprotein that induces critical signaling pathways. In this study, the role of rap1 in TTP-mediated invasion was investigated.
EXPERIMENTAL DESIGN: Using complementary approaches, we modulated TTP and altered expression of interleukin (IL)-6 and matrix metalloproteinase (MMP) 2/9, which were quantified by ELISA and zymogram. Invasion was evaluated in vitro using the oral-cancer-equivalent (OCE) three-dimensional model and in vivo in the chick chorioallantoic membrane (CAM). The role of rap1 and p38 were established using knockdown strategies.
RESULTS: Downregulation of TTP significantly increased invasion via secretion of MMP9/2 and IL-6. In the novel OCE and CAM invasion models of HNSCC, cells with downregulated TTP destroyed the basement membrane to invade the underlying connective tissue. Rap1 induces p38 mitogen-activated protein kinase (p38)-mediated inactivation of TTP. Inactive TTP enhances transcript stability via binding to the 3'-untranslated region (UTR). High IL-6 and MMP9 are prognostic for poor clinical outcomes in patients with HNSCC.
CONCLUSIONS: Targeting the rap1-p38-TTP cascade is an attractive novel treatment strategy in HNSCC to concurrently suppress multiple mediators of invasion.

Related: Apoptosis Head and Neck Cancers Head and Neck Cancers - Molecular Biology MMP2 MMP9: matrix metallopeptidase 9


Flacke JP, Flacke H, Appukuttan A, et al.
Type 10 soluble adenylyl cyclase is overexpressed in prostate carcinoma and controls proliferation of prostate cancer cells.
J Biol Chem. 2013; 288(5):3126-35 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
cAMP signaling plays an essential role in modulating the proliferation of different cell types, including cancer cells. Until now, the regulation of this pathway was restricted to the transmembrane class of adenylyl cyclases. In this study, significant overexpression of soluble adenylyl cyclase (sAC), an alternative source of cAMP, was found in human prostate carcinoma, and therefore, the contribution of this cyclase was investigated in the prostate carcinoma cell lines LNCaP and PC3. Suppression of sAC activity by treatment with the sAC-specific inhibitor KH7 or by sAC-specific knockdown mediated by siRNA or shRNA transfection prevented the proliferation of prostate carcinoma cells, led to lactate dehydrogenase release, and induced apoptosis. Cell cycle analysis revealed a significant rise in the G(2) phase population 12 h after sAC inhibition, which was accompanied by the down-regulation of cyclin B(1) and CDK1. sAC-dependent regulation of proliferation involves the EPAC/Rap1/B-Raf signaling pathway. In contrast, protein kinase A does not play a role. In conclusion, this study suggests a novel sAC-dependent signaling pathway that controls the proliferation of prostate carcinoma cells.

Related: Prostate Cancer


Kato M, Nakayama M, Agata M, Yoshida K
Gene expression levels of human shelterin complex and shelterin-associated factors regulated by the topoisomerase II inhibitors doxorubicin and etoposide in human cultured cells.
Tumour Biol. 2013; 34(2):723-33 [PubMed] Related Publications
Human telomerase reverse transcriptase (hTERT) is responsible for telomere elongation, and its activity is strongly related to the expression level of the hTERT gene; however, the transcriptional regulation of telomeric genes, which play a central role in telomere maintenance and protection by facilitating replication and regulating telomerase access, is poorly understood. In this study, we aimed to reveal the changes in the mRNA expression of six components of the shelterin complex and three shelterin complex-associated factors in topoisomerase II inhibitor-treated human cultured cells. Using a quantitative gene expression analysis, we found that a reduction in telomeric repeat-binding factor 1 (TRF1), protection of telomeres (POT1), and TRF1-interacting ankyrin-related ADP-ribose polymerase 1 (TNKS1) mRNAs was observed in etoposide- and doxorubicin-treated HeLa and U-2 OS cells, while an increased TRF2-interacting telomeric protein (RAP1) mRNA level was observed in U-2 OS cells. Furthermore, doxorubicin suppressed TRF1 and POT1 mRNAs in both Saos-2 and WI-38 cells and increased RAP1 mRNA in WI-38 cells. In agreement with the results obtained in the quantitative gene expression analysis in U-2 OS cells, the topoisomerase II inhibitors negatively and positively regulated the POT1 and RAP1 gene promoters, respectively. Taken together, these results suggest the successful identification of unique topoisomerase II inhibitor-inducible telomeric genes and provide mechanistic insight into the regulation of telomeric gene expression by chemotherapeutic agents.

Related: Bone Cancers Doxorubicin Etoposide Osteosarcoma POT1


Niola F, Zhao X, Singh D, et al.
Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis.
J Clin Invest. 2013; 123(1):405-17 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
High-grade gliomas (HGGs) are incurable brain tumors that are characterized by the presence of glioma-initiating cells (GICs). GICs are essential to tumor aggressiveness and retain the capacity for self-renewal and multilineage differentiation as long as they reside in the perivascular niche. ID proteins are master regulators of stemness and anchorage to the extracellular niche microenvironment, suggesting that they may play a role in maintaining GICs. Here, we modeled the probable therapeutic impact of ID inactivation in HGG by selective ablation of Id in tumor cells and after tumor initiation in a new mouse model of human mesenchymal HGG. Deletion of 3 Id genes induced rapid release of GICs from the perivascular niche, followed by tumor regression. GIC displacement was mediated by derepression of Rap1gap and subsequent inhibition of RAP1, a master regulator of cell adhesion. We identified a signature module of 5 genes in the ID pathway, including RAP1GAP, which segregated 2 subgroups of glioma patients with markedly different clinical outcomes. The model-informed survival analysis together with genetic and functional studies establish that ID activity is required for the maintenance of mesenchymal HGG and suggest that pharmacological inactivation of ID proteins could serve as a therapeutic strategy.


Chen CH, Chuang HC, Huang CC, et al.
Overexpression of Rap-1A indicates a poor prognosis for oral cavity squamous cell carcinoma and promotes tumor cell invasion via Aurora-A modulation.
Am J Pathol. 2013; 182(2):516-28 [PubMed] Related Publications
The functions of Rap-1A in oral carcinogenesis are largely unexplored. In this study, we examined the expression of Rap-1A at different malignant stages of oral cavity squamous cell carcinoma (OCSCC). Semiquantitative RT-PCR, quantitative RT-PCR, and Western blotting were used to evaluate Rap-1A mRNA and protein expressions, respectively, in paired OCSCC patient specimens. To determine the possible correlation between Rap-1A expression and various clinical characteristics, 256 samples from patients with OCSCC were evaluated by immunohistochemical staining. Strong Rap-1A expression was a significant prognostic marker and predictor of aggressive OCSCC. The overall and disease-specific 5-year survival rates were significantly correlated with strong expression of Rap-1A (P < 0.001). Functionally, overexpressed Rap-1A could promote oral cancer cell migration and invasion by Transwell chambers and wound healing assay. Conversely, the suppression of Rap-1A expression using Rap-1A-mediated siRNA was sufficient to decrease cell motility. Furthermore, our data also illustrated that Aurora-A could not only induce mRNA and protein expressions of Rap-1A for enhancing cancer cell motility but also co-localize and form a complex with Rap-1A in the oral cancer cell line. Finally, immunohistochemical staining, indirect immunofluorescence, and Western blotting analysis of human aggressive OCSCC specimens revealed a significantly positive correlation between Rap-1A and Aurora-A expression. Taken together, our results suggest that the Aurora-A/Rap-1A pathway is associated with survival, tumor progression, and metastasis of OCSCC patients.

Related: Oral Cancer


Ahmed SM, Thériault BL, Uppalapati M, et al.
KIF14 negatively regulates Rap1a-Radil signaling during breast cancer progression.
J Cell Biol. 2012; 199(6):951-67 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
The small GTPase Rap1 regulates inside-out integrin activation and thereby influences cell adhesion, migration, and polarity. Several Rap1 effectors have been described to mediate the cellular effects of Rap1 in a context-dependent manner. Radil is emerging as an important Rap effector implicated in cell spreading and migration, but the molecular mechanisms underlying its functions are unclear. We report here that the kinesin KIF14 associates with the PDZ domain of Radil and negatively regulates Rap1-mediated inside-out integrin activation by tethering Radil on microtubules. The depletion of KIF14 led to increased cell spreading, altered focal adhesion dynamics, and inhibition of cell migration and invasion. We also show that Radil is important for breast cancer cell proliferation and for metastasis in mice. Our findings provide evidence that the concurrent up-regulation of Rap1 activity and increased KIF14 levels in several cancers is needed to reach optimal levels of Rap1-Radil signaling, integrin activation, and cell-matrix adhesiveness required for tumor progression.

Related: Breast Cancer Signal Transduction KIF14


He M, Bian B, Gesuwan K, et al.
Telomere length is shorter in affected members of families with familial nonmedullary thyroid cancer.
Thyroid. 2013; 23(3):301-7 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
BACKGROUND: The theory that short telomere length and genetic defects in maintaining telomere length are associated with familial nonmedullary thyroid cancer (FNMTC) is controversial. Thus, the aim of this study was to determine whether telomere length and genes involved in maintaining telomere length are altered in FNMTC.
METHODS: Blood samples were collected from 44 members (13 affected and 31 unaffected) of six families with FNMTC and from 60 controls. Quantitative polymerase chain reaction (Q-PCR) and reverse transcription PCR were performed to analyze relative telomere length (RTL), gene copy number, and mRNA expression of telomerase reverse transcriptase (hTERT), telomere repeat binding factor 1 (TRF1), telomere repeat binding factor 2 (TRF2), repressor activator protein 1 (RAP1), TRF1 interacting nuclear factor 2 (TIN2), tripeptidyl peptidase 1 (TPP1), and protection of telomere 1 (POT1).
RESULTS: Affected members had shorter RTL, as compared with unaffected members (0.98 vs. 1.23, p<0.01). There was no significant difference in hTERT, TRF1, TRF2, RAP1, TIN2, TPP1, and POT1 gene copy number or mRNA expression between affected and unaffected members.
CONCLUSIONS: RTL is shorter in affected members with FNMTC but is not associated with altered copy number or expression in hTERT, TRF1, TRF2, RAP1, TIN2, TPP1, and POT1. The small differences in RTL preclude the utility of RTL as a marker for FNMTC in at-risk individuals.

Related: Thyroid Cancer


Coló GP, Hernández-Varas P, Lock J, et al.
Focal adhesion disassembly is regulated by a RIAM to MEK-1 pathway.
J Cell Sci. 2012; 125(Pt 22):5338-52 [PubMed] Related Publications
Cell migration and invasion require regulated turnover of integrin-dependent adhesion complexes. Rap1-GTP-interacting adaptor molecule (RIAM) is an adaptor protein that mediates talin recruitment to the cell membrane, and whose depletion leads to defective melanoma cell migration and invasion. In this study, we investigated the potential involvement of RIAM in focal adhesion (FA) dynamics. RIAM-depleted melanoma and breast carcinoma cells displayed an increased number, size and stability of FAs, which accumulated centrally at the ventral cell surface, a phenotype caused by defective FA disassembly. Impairment in FA disassembly resulting from RIAM knockdown correlated with deficient integrin-dependent mitogen-activated protein kinase kinase (MEK)-Erk1/2 activation and, importantly, overexpression of constitutively active MEK resulted in rescue of FA disassembly and recovery of cell invasion. Furthermore, RIAM-promoted Ras homologue gene family, member A (RhoA) activation following integrin engagement was needed for subsequent Erk1/2 activation. In addition, RhoA overexpression partially rescued the FA phenotype in RIAM-depleted cells, also suggesting a functional role for RhoA downstream of RIAM, but upstream of Erk1/2. RIAM knockdown also led to enhanced phosphorylation of paxillin Tyr118 and Tyr31. However, expression of phosphomimetic and nonphosphorylatable mutants at these paxillin residues indicated that paxillin hyperphosphorylation is a subsequent consequence of the blockade of FA disassembly, but does not cause the FA phenotype. RIAM depletion also weakened the association between FA proteins, suggesting that it has important adaptor roles in the correct assembly of adhesion complexes. Our data suggest that integrin-triggered, RIAM-dependent MEK activation represents a key feedback event required for efficient FA disassembly, which could help explain the role of RIAM in cell migration and invasion.

Related: Melanoma RHOA


Wang K, Li J, Guo H, et al.
MiR-196a binding-site SNP regulates RAP1A expression contributing to esophageal squamous cell carcinoma risk and metastasis.
Carcinogenesis. 2012; 33(11):2147-54 [PubMed] Related Publications
Polymorphisms in 3' untranslated region (UTR) of cancer-related genes might affect regulation by microRNA (miRNA) and contribute to carcinogenesis. In this study, we screened several single nucleotide polymorphisms (SNPs) in 3'UTR of cancer-related genes and investigated their effects on the risk of esophageal squamous cell carcinoma (ESCC). First, we used SNaPshot assay to genotype seven 3'UTR SNPs in 537 ESCC cases and 608 normal controls in a Chinese Han population and found that SNP rs6573 in 3'UTR of RAS-related proteins (RAP1A) was significantly associated with ESCC risk [P = 0.02, odds ratio (OR) = 0.43; 95% confidence interval (CI): 0.21-0.91] and pathologic stage (P = 0.03, OR = 1.89; 95% CI: 1.06-3.36). A putative binding site for miRNA-196a (miR-196a) exists in the 3'UTR of RAP1A, and the genetic variant, rs6573 A→C, is present in this binding region. We confirmed that miR-196a regulated the expression of RAP1A by luciferase reporter assay and that the regulation was affected by the RAP1A genotype. SNP rs6573 A to C change interfere in the interaction of miR-196a binding to RAP1A 3'UTR, resulting in higher constitutive expression of RAP1A. Moreover, we observed that RAP1A was overexpressed in the majority of ESCC tissues and correlated with RAP1A genotype and lymph node metastasis. In vitro study indicated RAP1A might function as a promoter for esophageal cancer cell migration and invasion through matrix metalloproteinase 2. Our study highlights RAP1A and SNP rs6573 functioning as potential personal diagnostic and prognosis markers for ESCC.

Related: Cancer of the Esophagus Esophageal Cancer MMP2


Du L, Subauste MC, DeSevo C, et al.
miR-337-3p and its targets STAT3 and RAP1A modulate taxane sensitivity in non-small cell lung cancers.
PLoS One. 2012; 7(6):e39167 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
NSCLC (non-small cell lung cancer) often exhibits resistance to paclitaxel treatment. Identifying the elements regulating paclitaxel response will advance efforts to overcome such resistance in NSCLC therapy. Using in vitro approaches, we demonstrated that over-expression of the microRNA miR-337-3p sensitizes NCI-H1155 cells to paclitaxel, and that miR-337-3p mimic has a general effect on paclitaxel response in NSCLC cell lines, which may provide a novel adjuvant strategy to paclitaxel in the treatment of lung cancer. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p on paclitaxel sensitivity. Further investigation showed that miR-337-3p mimic also sensitizes cells to docetaxel, another member of the taxane family, and that STAT3 levels are significantly correlated with taxane resistance in lung cancer cell lines, suggesting that endogenous STAT3 expression is a determinant of intrinsic taxane resistance in lung cancer. The identification of a miR-337-3p as a modulator of cellular response to taxanes, and STAT3 and RAP1A as regulatory targets which mediate that response, defines a novel regulatory pathway modulating paclitaxel sensitivity in lung cancer cells, which may provide novel adjuvant strategies along with paclitaxel in the treatment of lung cancer and may also provide biomarkers for predicting paclitaxel response in NSCLC.

Related: Non-Small Cell Lung Cancer Paclitaxel


Dong X, Tang W, Stopenski S, et al.
RAP1GAP inhibits cytoskeletal remodeling and motility in thyroid cancer cells.
Endocr Relat Cancer. 2012; 19(4):575-88 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
The functional significance of decreased RAP1GAP protein expression in human tumors is unclear. To identify targets of RAP1GAP downregulation in the thyroid gland, RAP1 and RAP2 protein expression in human thyroid cells and in primary thyroid tumors were analyzed. RAP1GAP and RAP2 were co-expressed in normal thyroid follicular cells. Intriguingly, RAP1 was not detected in normal thyroid cells, although it was detected in papillary thyroid carcinomas, which also expressed RAP2. Both RAP proteins were detected at the membrane in papillary thyroid tumors, suggesting that they are activated when RAP1GAP is downregulated. To explore the functional significance of RAP1GAP depletion, RAP1GAP was transiently expressed at the lowest level that is sufficient to block endogenous RAP2 activity in papillary and anaplastic thyroid carcinoma cell lines. RAP1GAP impaired the ability of cells to spread and migrate on collagen. Although RAP1GAP had no effect on protein tyrosine phosphorylation in growing cells, RAP1GAP impaired phosphorylation of focal adhesion kinase and paxillin at sites phosphorylated by SRC in cells acutely plated on collagen. SRC activity was increased in suspended cells, where it was inhibited by RAP1GAP. Inhibition of SRC kinase activity impaired cell spreading and motility. These findings identify SRC as a target of RAP1GAP depletion and suggest that the downregulation of RAP1GAP in thyroid tumors enhances SRC-dependent signals that regulate cellular architecture and motility.

Related: Thyroid Cancer RAP2A


Banerjee R, Russo N, Liu M, et al.
Rap1 and its regulatory proteins: the tumor suppressor, oncogene, tumor suppressor gene axis in head and neck cancer.
Small GTPases. 2012 Jul-Sep; 3(3):192-7 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer, globally. Previously, we showed that Rap1GAP is a tumor suppressor gene that inhibits tumor growth, but promotes invasion in SCCHN. In this work, we discuss the role of Rap1 and Rap1GAP in SCCHN progression in the context of a microRNA-oncogene-tumor suppressor gene axis, and investigate the role of Rap1GAP in EZH2-mediated invasion. Loss of expression of microRNA-101 in SCCHN leads to upregulation of EZH2, a histone methyltransferase. Overexpression of EZH2 silences Rap1GAP via methylation, thereby promoting activation of its target, Rap1. This microRNA-controlled activation of Rap1, via EZH2-mediated silencing of Rap1GAP, is a novel mechanism of Rap1 regulation. In two independent SCCHN cell lines, downregulation of EZH2 inhibits proliferation and invasion. In both cell lines, stable knockdown of EZH2 (shEZH2) recovers Rap1GAP expression and inhibits proliferation. However, siRNA-mediated knockdown of Rap1GAP in these cells rescues proliferation but not invasion. Thus, EZH2 promotes proliferation and invasion via Rap1GAP-dependent and -independent mechanisms, respectively. Although the studies presented here are in the context of SCCHN, our results may have broader implications, given that Rap1GAP acts as a tumor suppressor in pancreatic cancer, thyroid cancer, and melanoma.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology


Spina A, Sorvillo L, Di Maiolo F, et al.
Inorganic phosphate enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin via a p53-dependent pathway.
J Cell Physiol. 2013; 228(1):198-206 [PubMed] Related Publications
Osteosarcoma is the most common malignant primary bone tumor in children and adolescents. The clinical outcome for osteosarcoma remains discouraging despite aggressive surgery and intensive radiotherapy and chemotherapy regimens. Thus, novel therapeutic approaches are needed. Previously, we have shown that inorganic phosphate (Pi) inhibits proliferation and aggressiveness of human osteosarcoma U2OS cells identifying adenylate cyclase, beta3 integrin, Rap1, ERK1/2 as proteins whose expression and function are relevantly affected in response to Pi. In this study, we investigated whether Pi could affect chemosensitivity of osteosarcoma cells and the underlying molecular mechanisms. Here, we report that Pi inhibits proliferation of p53-wild type U2OS cells (and not of p53-null Saos and p53-mutant MG63 cells) by slowing-down cell cycle progression, without apoptosis occurrence. Interestingly, we found that Pi strongly enhances doxorubicin-induced cytotoxicity in U2OS, and not in Saos and MG63 cells, by apoptosis induction, as revealed by a marked increase of sub-G1 population, Bcl-2 downregulation, caspase-3 activation, and PARP cleavage. Remarkably, Pi/doxorubicin combination-induced cytotoxicity was accompanied by an increase of p53 protein levels and of p53 target genes mdm2, p21 and Bax, and was significantly reduced by the p53 inhibitor pifithrine-alpha. Moreover, the doxorubicin-induced cytotoxicity was associated with ERK1/2 pathway inhibition in response to Pi. Altogether, our data enforce the evidence of Pi as a novel signaling molecule capable of inhibiting ERK pathway and inducing sensitization to doxorubicin of osteosarcoma cells by p53-dependent apoptosis, implying that targeting Pi levels might represent a rational strategy for improving osteosarcoma therapy.

Related: Bone Cancers Doxorubicin Osteosarcoma TP53


Qiu T, Qi X, Cen J, Chen Z
Rap1GAP alters leukemia cell differentiation, apoptosis and invasion in vitro.
Oncol Rep. 2012; 28(2):622-8 [PubMed] Related Publications
Rap1GAP which regulates the GTP-GDP form switch of Rap1 is a member of the GTPase-activating protein (GAP) family and has recently received substantial attention. Rap1GAP is thought of as a putative tumor suppressor gene and plays an important role in human tumor progression including pancreatic cancer, thyroid cancer and melanoma. In the current study, we found that the expression of Rap1GAP was lower in acute myeloid leukemia (AML) patients compared to non-malignant blood disease patients. The expression of Rap1GAP was also low in HL-60, NB4, U937 and SHI-1 myeloid leukemia cell lines. Upregulated Rap1GAP in NB4 and HL-60 cells promoted cell differentiation induced by ATRA or TPA compared to the empty vector control cells. Furthermore, Rap1GAP-transfected cells also showed a higher rate of apoptosis in response to arsenic trioxide compared to the control counterpart cells. In addition, we found that increased expression of Rap1GAP promoted leukemia cell invasion may be due to matrix metalloproteinase 9 (MMP9). In conclusion, these results demonstrated that Rap1GAP promoted leukemia cell differentiation and apoptosis, but increased leukemia cell invasion in vitro.

Related: Apoptosis Acute Myeloid Leukemia (AML) MMP9: matrix metallopeptidase 9


Cheung HW, Du J, Boehm JS, et al.
Amplification of CRKL induces transformation and epidermal growth factor receptor inhibitor resistance in human non-small cell lung cancers.
Cancer Discov. 2011; 1(7):608-25 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
UNLABELLED: We previously identified a region of recurrent amplification on chromosome 22q11.21 in a subset of primary lung adenocarcinomas. Here we show that CRKL, encoding for an adaptor protein, is amplified and overexpressed in non-small cell lung cancer (NSCLC) cells that harbor 22q11.21 amplifications. Overexpression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death. Overexpression of CRKL in epidermal growth factor receptor (EGFR)-mutant cells induces resistance to gefitinib by activating extracellular signal-regulated kinase and AKT signaling. We identified CRKL amplification in an EGFR inhibitor-treated lung adenocarcinoma that was not present before treatment. These observations demonstrate that CRKL overexpression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.
SIGNIFICANCE: These studies credential CRKL as an oncogene in a subset of NSCLC. Overexpression of CRKL induces cell transformation and resistance to epidermal growth factor receptor inhibitor treatment and suggest that therapeutic interventions targeting CRKL may confer a clinical benefit in a defined subset of NSCLCs.

Related: Chromosome 22 Lung Cancer AKT1 Signal Transduction CRKL EGFR Gefitinib (Iressa)


Li X, Zhang R, Draheim KM, et al.
Structural basis for small G protein effector interaction of Ras-related protein 1 (Rap1) and adaptor protein Krev interaction trapped 1 (KRIT1).
J Biol Chem. 2012; 287(26):22317-27 [PubMed] Article available free on PMC after 20/06/2015 Related Publications
Cerebral cavernous malformations (CCMs) affect 0.1-0.5% of the population resulting in leaky vasculature and severe neurological defects. KRIT1 (Krev interaction trapped-1) mutations associate with ∼40% of familial CCMs. KRIT1 is an effector of Ras-related protein 1 (Rap1) GTPase. Rap1 relocalizes KRIT1 from microtubules to cell membranes to impact integrin activation, potentially important for CCM pathology. We report the 1.95 Å co-crystal structure of KRIT1 FERM domain in complex with Rap1. Rap1-KRIT1 interaction encompasses an extended surface, including Rap1 Switch I and II and KRIT1 FERM F1 and F2 lobes. Rap1 binds KRIT1-F1 lobe using a GTPase-ubiquitin-like fold interaction but binds KRIT1-F2 lobe by a novel interaction. Point mutagenesis confirms the interaction. High similarity between KRIT1-F2/F3 and talin is revealed. Additionally, the mechanism for FERM domains acting as GTPase effectors is suggested. Finally, structure-based alignment of each lobe suggests classification of FERM domains as ERM-like and TMFK-like (talin-myosin-FAK-KRIT-like) and that FERM lobes resemble domain "modules."

Related: Signal Transduction


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Cite this page: Cotterill SJ. RAP1A, Cancer Genetics Web: http://www.cancerindex.org/geneweb/RAP1A.htm Accessed: date

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