EPS15

Gene Summary

Gene:EPS15; epidermal growth factor receptor pathway substrate 15
Aliases: AF1P, AF-1P, MLLT5
Location:1p32
Summary:This gene encodes a protein that is part of the EGFR pathway. The protein is present at clatherin-coated pits and is involved in receptor-mediated endocytosis of EGF. Notably, this gene is rearranged with the HRX/ALL/MLL gene in acute myelogeneous leukemias. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:epidermal growth factor receptor substrate 15
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
Show (19)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 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.

  • Proteins
  • Calcium-Binding Proteins
  • Phosphoproteins
  • Recombinant Fusion Proteins
  • Epidermal Growth Factor Receptor
  • Base Sequence
  • Amino Acid Sequence
  • RTPCR
  • Tyrosine
  • Polymerase Chain Reaction
  • MLL
  • Chromosome 11
  • Young Adult
  • Protein Structure, Tertiary
  • Proto-Oncogenes
  • Western Blotting
  • DNA-Binding Proteins
  • Transcription Factors
  • Cloning, Molecular
  • Chromosome 1
  • Sequence Homology
  • Neoplastic Cell Transformation
  • Cell Cycle
  • Neoplasm Invasiveness
  • DNA Primers
  • Chromosome Breakage
  • EPS15
  • KMT2A
  • Acute Lymphocytic Leukaemia
  • Intracellular Signaling Peptides and Proteins
  • Cancer Gene Expression Regulation
  • Zinc Fingers
  • Signal Transducing Adaptor Proteins
  • Leukaemia
  • Molecular Sequence Data
  • Oncogene Fusion Proteins
  • Twins, Monozygotic
  • Cancer RNA
  • Gene Expression Profiling
  • Acute Myeloid Leukaemia
  • Translocation
  • Signal Transduction
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

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

Latest Publications: EPS15 (cancer-related)

Chukkapalli S, Amessou M, Dekhil H, et al.
Ehd3, a regulator of vesicular trafficking, is silenced in gliomas and functions as a tumor suppressor by controlling cell cycle arrest and apoptosis.
Carcinogenesis. 2014; 35(4):877-85 [PubMed] Related Publications
EHD3 [Eps15 homology (EH) domain-containing protein 3] is a protein that resides in tubular and vesicular membrane structures and participates in endocytic recycling, although all its functions are unknown. Since Ehd3 is most abundantly expressed in brain tissues, we examined its role in brain cancer progression. Using immunohistochemistry, we report loss of EHD3 expression in gliomas, including low-grade astrocytomas, suggesting that this is an early event in gliomagenesis. EHD3 expression is also very low in most of glioma cell lines tested. In two cell lines, a bisulfite sequencing method identifies promoter hypermethylation as a mechanism of Ehd3 silencing, and its expression was restored by the demethylating agent 5-Azacytidine. Doxycycline-inducible restoration of EHD3 expression to glioma cells decreases their growth and invasiveness and induces cell cycle arrest and apoptosis. Furthermore, shRNA-mediated Ehd3 silencing increases cell growth. Using a xenograft model, we demonstrate Ehd3 growth inhibitory functions in glioma cells in vivo. We suggest that Ehd3 functions as a tumor suppressor gene and loss of its expression is a very common event in gliomas. This is the first study to highlight the importance of a member of the C-terminal EHD proteins in cancer and to link their functions to the cell cycle and apoptosis.

Zhi X, Chen C
WWP1: a versatile ubiquitin E3 ligase in signaling and diseases.
Cell Mol Life Sci. 2012; 69(9):1425-34 [PubMed] Related Publications
WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a multifunction protein containing an N-terminal C2 domain, four tandem WW domains for substrate binding, and a C-terminal catalytic HECT domain for ubiquitin transferring. WWP1 has been suggested to function as the E3 ligase for several PY motif-containing proteins, such as Smad2, KLF5, p63, ErbB4/HER4, RUNX2, JunB, RNF11, SPG20, and Gag, as well as several non-PY motif containing proteins, such as TβR1, Smad4, KLF2, and EPS15. WWP1 regulates a variety of cellular biological processes including protein trafficking and degradation, signaling, transcription, and viral budding. WWP1 has been implicated in several diseases, such as cancers, infectious diseases, neurological diseases, and aging. In this review article, we extensively summarize the current knowledge of WWP1 with special emphasis on the roles and action of mechanism of WWP1 in signaling and human diseases.

De Braekeleer E, Meyer C, Douet-Guilbert N, et al.
Identification of MLL partner genes in 27 patients with acute leukemia from a single cytogenetic laboratory.
Mol Oncol. 2011; 5(6):555-63 [PubMed] Related Publications
Chromosomal rearrangements involving the MLL gene have been associated with many different types of hematological malignancies. Fluorescent in situ hybridization with a panel of probes coupled with long distance inverse-PCR was used to identify chromosomal rearrangements involving the MLL gene. Between 1995 and 2010, 27 patients with an acute leukemia were found to have a fusion gene involving MLL. All seven ALL patients with B cell acute lymphoblastic leukemia were characterized by the MLL/AFF1 fusion gene resulting from a translocation (5 patients) or an insertion (2 patients). In the 19 AML patients with acute myeloblastic leukemia, 31.6% of all characterized MLL fusion genes were MLL/MLLT3, 21.1% MLL/ELL, 10.5% MLL/MLLT6 and 10.5% MLL/EPS15. Two patients had rare or undescribed fusion genes, MLL/KIAA0284 and MLL/FLNA. Seven patients (26%) had a complex chromosomal rearrangement (three-way translocations, insertions, deletions) involving the MLL gene. Splicing fusion genes were found in three patients, leading to a MLL/EPS15 fusion in two and a MLL/ELL fusion in a third patient. This study showed that fusion involving the MLL gene can be generated through various chromosomal rearrangements such as translocations, insertions and deletions, some being complex or cryptic. A systematic approach should be used in all cases of acute leukemia starting with FISH analyses using a commercially available MLL split signal probe. Then, the analysis has to be completed, if necessary, by further molecular cytogenetic and genomic PCR methods.

Bonuccelli G, Casimiro MC, Sotgia F, et al.
Caveolin-1 (P132L), a common breast cancer mutation, confers mammary cell invasiveness and defines a novel stem cell/metastasis-associated gene signature.
Am J Pathol. 2009; 174(5):1650-62 [PubMed] Free Access to Full Article Related Publications
Here we used the Met-1 cell line in an orthotopic transplantation model in FVB/N mice to dissect the role of the Cav-1(P132L) mutation in human breast cancer. Identical experiments were performed in parallel with wild-type Cav-1. Cav-1(P132L) up-regulated the expression of estrogen receptor-alpha as predicted, because only estrogen receptor-alpha-positive patients have been shown to harbor Cav-1(P132L) mutations. In the context of primary tumor formation, Cav-1(P132L) behaved as a loss-of-function mutation, lacking any tumor suppressor activity. In contrast, Cav-1(P132L) caused significant increases in cell migration, invasion, and experimental metastasis, consistent with a gain-of-function mutation. To identify possible molecular mechanism(s) underlying this invasive gain-of-function activity, we performed unbiased gene expression profiling. From this analysis, we show that the Cav-1(P132L) expression signature contains numerous genes that have been previously associated with cell migration, invasion, and metastasis. These include i) secreted growth factors and extracellular matrix proteins (Cyr61, Plf, Pthlh, Serpinb5, Tnc, and Wnt10a), ii) proteases that generate EGF and HGF (Adamts1 and St14), and iii) tyrosine kinase substrates and integrin signaling/adapter proteins (Akap13, Cdcp1, Ddef1, Eps15, Foxf1a, Gab2, Hs2st1, and Itgb4). Several of the P132L-specific genes are also highly expressed in stem/progenitor cells or are associated with myoepithelial cells, suggestive of an epithelial-mesenchymal transition. These results directly support clinical data showing that patients harboring Cav-1 mutations are more likely to undergo recurrence and metastasis.

Meyer C, Kowarz E, Hofmann J, et al.
New insights to the MLL recombinome of acute leukemias.
Leukemia. 2009; 23(8):1490-9 [PubMed] Related Publications
Chromosomal rearrangements of the human MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemias. These patients need to be identified, treated appropriately and minimal residual disease was monitored by quantitative PCR techniques. Genomic DNA was isolated from individual acute leukemia patients to identify and characterize chromosomal rearrangements involving the human MLL gene. A total of 760 MLL-rearranged biopsy samples obtained from 384 pediatric and 376 adult leukemia patients were characterized at the molecular level. The distribution of MLL breakpoints for clinical subtypes (acute lymphoblastic leukemia, acute myeloid leukemia, pediatric and adult) and fused translocation partner genes (TPGs) will be presented, including novel MLL fusion genes. Combined data of our study and recently published data revealed 104 different MLL rearrangements of which 64 TPGs are now characterized on the molecular level. Nine TPGs seem to be predominantly involved in genetic recombinations of MLL: AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, MLLT4/AF6, ELL, EPS15/AF1P, MLLT6/AF17 and SEPT6, respectively. Moreover, we describe for the first time the genetic network of reciprocal MLL gene fusions deriving from complex rearrangements.

Parachoniak CA, Park M
Distinct recruitment of Eps15 via Its coiled-coil domain is required for efficient down-regulation of the met receptor tyrosine kinase.
J Biol Chem. 2009; 284(13):8382-94 [PubMed] Free Access to Full Article Related Publications
Down-regulation of receptor tyrosine kinases (RTK) through receptor internalization and degradation is critical for appropriate biological responses. The hepatocyte growth factor RTK (also known as Met) regulates epithelial remodeling, dispersal, and invasion and is deregulated in human cancers. Impaired down-regulation of the Met RTK leads to sustained signaling, cell transformation, and tumorigenesis, hence understanding mechanisms that regulate this process is crucial. Here we report that, following Met activation, the endocytic adaptor protein, Eps15, is recruited to the plasma membrane and becomes both tyrosine-phosphorylated and ubiquitinated. Recruitment of Eps15 requires Met receptor kinase activity and involves two distinct Eps15 domains. Unlike previous reports for the EGF RTK, which requires the Eps15 ubiquitin interacting motif, recruitment of Eps15 to Met involves the coiled-coil domain of Eps15 and the signaling adaptor molecule, Grb2, which binds through a proline-rich motif in the third domain of Eps15. Expression of the coiled-coil domain is sufficient to displace the wild-type Eps15 protein complex from Met, resulting in loss of tyrosine phosphorylation of Eps15. Knockdown of Eps15 results in delayed Met degradation, which can be rescued by expression of Eps15 WT but not an Eps15 mutant lacking the coiled-coil domain, identifying a role for this domain in Eps15-mediated Met down-modulation. This study demonstrates a new mechanism of recruitment for Eps15 downstream of the Met receptor, involving the coiled-coil domain of Eps15 as well as interaction of Eps15 with Grb2. This highlights distinct regulation of Eps15 recruitment and the diversity and adaptability of endocytic molecules in promoting RTK trafficking.

Niehof M, Borlak J
EPS15R, TASP1, and PRPF3 are novel disease candidate genes targeted by HNF4alpha splice variants in hepatocellular carcinomas.
Gastroenterology. 2008; 134(4):1191-202 [PubMed] Related Publications
BACKGROUND & AIMS: The orphan nuclear receptor HNF4alpha is a member of the hepatic transcription factor network. This protein plays a pivotal role in liver development and hepatocellular differentiation. Nine splice variants have been identified, some of which are specifically regulated in disease. The role of HNF4alpha splice variants in hepatocellular carcinomas (HCC) is unknown. Here, we report an identification of novel candidate genes targeted by splice variants of HNF4alpha.
METHODS: We used chromatin immunoprecipitation followed by cloning and sequencing of DNA. Expression of HNF4alpha P1 and P2 promoter-driven isoforms and of genes targeted by HNF4alpha were analyzed by quantitative reverse-transcription polymerase chain reaction, Western blotting, electrophoretic mobility shift assay, and immunohistochemistry.
RESULTS: We observed a remarkable switch in gene and protein expression from P1 to P2 promoter-driven fetal isoforms of HNF4alpha in transgenic livers and HCCs of epidermal growth factor (EGF) overexpressing mice and in human HCCs. We further identified EGF-receptor substrate (EPS15R), related EPS15, the premessenger RNA processing factor 3 (PRPF3), and taspase 1 (TASP1) as novel HNF4alpha disease regulated genes with induced expression in mouse and in human HCCs. We suggest EPS15 and EPS15R mediated internalization of activated EGF receptor to result in receptor recycling as to reinforce the proliferative response to EGF. Regulation of the type 2 asparaginase TASP1 and of the splicing factor PRPF3 further documents a switch to fetal liver programs in HCC.
CONCLUSIONS: We report induction of P2 promoter-driven HNF4alpha splice variants and regulation of disease candidate genes in EGF-induced mouse and human HCC.

Roy UK, Rial NS, Kachel KL, Gerner EW
Activated K-RAS increases polyamine uptake in human colon cancer cells through modulation of caveolar endocytosis.
Mol Carcinog. 2008; 47(7):538-53 [PubMed] Free Access to Full Article Related Publications
Endocytic pathways have been implicated in polyamine transport in mammalian cells, but specific mechanisms have not been described. We have shown that expression of a dominant negative (DN) form of the GTPase Dynamin, but not Eps15, diminished polyamine uptake in colon cancer cells indicating a caveolar and nonclathrin uptake mode. Polyamines co-sediment with lipid raft/caveolin-1 rich fractions, of the plasma membrane in a sucrose density gradient. Knock down of caveolin-1 significantly increased polyamine uptake. Conversely, ectopic expression of this protein resulted in diminished polyamine uptake. We also found that presence of an activated K-RAS oncogene significantly increased polyamine uptake by colon cancer cells. This effect is through an increase in caveolin-1 phosphorylation at tyrosine residue 14. Caveolin-1 is a negative regulator of caveolar endocytosis and phosphorylation in a K-RAS dependent manner leads to an increase in caveolar endocytosis. In cells expressing wild type K-RAS, addition of exogenous uPA was sufficient to stimulate caveolar endocytosis of polyamines. This effect was abrogated by the addition of a SRC kinase inhibitor. These data indicate that polyamine transport follows a dynamin-dependent and clathrin-independent endocytic uptake route, and this route is positively regulated by the oncogenic expression of K-RAS in a caveolin-1 dependent manner.

Agelopoulos K, Kersting C, Korsching E, et al.
Egfr amplification specific gene expression in phyllodes tumours of the breast.
Cell Oncol. 2007; 29(6):443-51 [PubMed] Related Publications
BACKGROUND: Recently, we were able to show that amplifications of the epidermal growth factor receptor (egfr) gene and the overexpression of EGFR were associated with the initiation and progression of phyllodes tumours.
METHODS: In order to gain further insights into regulation mechanisms associated with egfr amplifications and EGFR expression in phyllodes tumours, we performed global gene expression analysis (Affymetrix A133.2) on a series of 10 phyllodes tumours, of these three with and seven without amplifications of an important regulatory repeat in intron 1 of egfr (CA-SSR I). The results were verified and extended by means of immunohistochemistry using the tissue microarray method on an extensively characterized series of 58 phyllodes tumours with antibodies against caveolin-1, eps15, EGF, TGF-alpha, pErk, pAkt and mdm2.
RESULTS: We were able to show that the presence of egfr CA-SSR I amplifications in phyllodes tumours was associated with 230 differentially expressed genes. Caveolin-1 and eps15, involved in EGFR turnover and signalling, were regulated differentially on the RNA and protein level proportionally to egfr gene dosage. Further immunohistochemical analysis revealed that the expression of caveolin-1 and eps15 were also significantly correlated with the expression of pAkt (p<0.05), pERK (p<0.05), mdm2 (p<0.01) and EGF (p<0.001 for caveolin-1). Eps15 and pERK were further associated with tumour grade (p<0.01 and p<0.001, respectively).
CONCLUSION: Our results show that amplifications within regulatory sequences of egfr are associated with the expression of eps15 and caveolin-1, indicating an increased turnover of EGFR. The interplay between EGFR and caveolin-1, eps15, pAkt, mdm2 and pERK therefore seems to present a major molecular pathway in carcinogenesis and progression of breast phyllodes tumours.

Sagawa M, Shimizu T, Shimizu T, et al.
Establishment of a new human acute monocytic leukemia cell line TZ-1 with t(1;11)(p32;q23) and fusion gene MLL-EPS15.
Leukemia. 2006; 20(9):1566-71 [PubMed] Related Publications
Human leukemia cell lines are of great value in investigating basic and applied aspects of cell biology and clinical medicine. There have been 37 leukemia cell lines carrying 11q23 translocation and MLL rearrangements; however, cell lines harboring with t(1;11)(p32;q23) have not been established. We report here for the first time a new acute monocytic leukemia (AMoL) cell line with t(1;11)(p32;q23), designated TZ-1, and herein describe its biological characteristics. Mononuclear cells isolated from the ascites from a patient with AMoL (French-American-British classification; acute myeloid leukemia M5a) were isolated and passaged by liquid culture medium for a year. TZ-1 cells revealed typical monocytic features in morphology and had a t(1;11)(p32;q23) translocation. The immunoprofiling as determined by flow cytometry showed that TZ-1 cells are positive for myeloid and monocytic markers with lymphoid-associated markers. Fluorescence in situ hybridization and reverse transcription-polymerase chain reaction analyses revealed MLL-EPS15 fusion transcript and protein. Taken together, these results suggest that TZ-1 is a new monocytic leukemia cell line with t(1;11) translocation and fusion gene MLL-EPS15. The established cell line, TZ-1, could provide a valuable model in the analysis of the pathogenesis of MLL-EPS15-positive leukemia and in the development of new agents for this type of leukemia.

Dörrschuck A, Schmidt A, Schnürer E, et al.
CD8+ cytotoxic T lymphocytes isolated from allogeneic healthy donors recognize HLA class Ia/Ib-associated renal carcinoma antigens with ubiquitous or restricted tissue expression.
Blood. 2004; 104(8):2591-9 [PubMed] Related Publications
Allogeneic hematopoietic stem cell transplantation can induce considerable tumor remissions in metastatic renal-cell carcinoma (RCC) patients. The precise effector mechanisms mediating these graft-versus-tumor reactions are unknown. We studied RCC-directed CD8(+) T-cell responses in blood lymphocytes of healthy individuals matched with established RCC cell lines for HLA-class I. In 21 of 22 allogeneic mixed lymphocyte/tumor-cell cultures (MLTCs), RCC-reactive cytotoxic T-lymphocytes (CTLs) were readily obtained. From MLTCs, 121 CD8(+) CTL clones with memory phenotype were isolated. Their anti-RCC reactivity was restricted by multiple classical HLA-Ia molecules, in particular by HLA-A2, -A3, -B7, -B44, -Cw7, and by a nonclassical HLA-Ib determinant. Extensive cross-reactivity analyses on a broad target panel identified CTLs that recognize antigens with expression restricted to renal tissue or to renal and colon tumors. Other CTLs were directed against antigens with broader tissue distribution being expressed in various epithelial and nonepithelial tumors or, additionally, in hematopoietic cells. With microcapillary liquid chromatography and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)/TOF mass spectrometry, we identified the HLA-A*0301-associated nonpolymorphic peptide KLPNSVLGR encoded by the ubiquitously expressed Eps15 homology domain-containing 2 gene as a CTL target. Defining human RCC antigens recognized by alloreactive CTLs may allow to improve the specificity and efficiency of allogeneic cell therapy (eg, specific donor-lymphocyte infusions or vaccination) in metastatic RCC patients.

Tsujioka T, Wada H, Yamamori S, et al.
MLL/AF-1p fusion in therapy-related early pre-B acute lymphoblastic leukemia with t(1;11)(p32;q23) translocation developing in the relapse phase of acute promyelocytic leukemia.
Int J Hematol. 2003; 78(5):439-42 [PubMed] Related Publications
We report the development of therapy-related early pre-B acute lymphoblastic leukemia in a patient administered a topoisomerase II inhibitor, etoposide, a consolidation therapy agent for acute promyelocytic leukemia. Our case is of interest because of simultaneous relapse of the original leukemia and onset of therapy-related leukemia and relatively rare t(1;11)(p32;q23) translocation with confirmed MLL/AF-1p fusion. This case suggests that careful monitoring for MLL gene rearrangements is necessary after administration of topoisomerase II inhibitors.

So CW, Lin M, Ayton PM, et al.
Dimerization contributes to oncogenic activation of MLL chimeras in acute leukemias.
Cancer Cell. 2003; 4(2):99-110 [PubMed] Related Publications
MLL is a histone methyltransferase that can be converted into an oncoprotein by acquisition of transcriptional effector domains following heterologous protein fusions with a variety of nuclear transcription factors, cofactors, or chromatin remodeling proteins in acute leukemias. Here we demonstrate an alternative mechanism for activation of MLL following fusions with proteins (AF1p/Eps15 and GAS7) that normally reside in the cytoplasm. The coiled-coil oligomerization domains of these proteins are necessary and sufficient for leukemogenic transformation induced by the respective MLL fusion proteins. Furthermore, homodimerization of MLL by synthetic dimerization modules mimics bona fide MLL fusion proteins resulting in Hox gene activation and enhanced self-renewal of hematopoietic progenitors. Our studies support an oligomerization-dependent mechanism for oncogenic conversion of MLL, presumably in part by recruitment of accessory factors through the dimerized MLL moiety of the chimeric protein.

Liu LX, Liu ZH, Jiang HC, et al.
Gene expression profiles of hepatoma cell line HLE.
World J Gastroenterol. 2003; 9(4):683-7 [PubMed] Related Publications
AIM: To investigate the global gene expression of cancer related genes in hepatoma cell line HLE using Atlas Human Cancer Array membranes with 588 well-characterized human genes related with cancer and tumor biology.
METHODS: Hybridization of cDNA blotting membrane was performed with (32)P-labeled cDNA probes synthesized from RNA isolated from Human hepatoma cell line HLE and non-cirrhotic normal liver which was liver transplantation donor. AtlasImage, a software specific to array, was used to analyze the result. The expression pattern of some genes identified by Atlas arrays hybridization was confirmed by reverse transcription polymerase chain reaction (RT-PCR) in 24 pairs of specimens and Northern blot of 4 pairs of specimens.
RESULTS: The differential expression of cell cycle/growth regulator in hepatocellular carcinoma (HCC) showed a stronger tendency toward cell proliferation with more than 1.5-fold up-regulation of Cyclin C, ERK5, ERK6, E2F-3, TFDP-2 and CK4. The anti-apoptotic factors such as Akt-1 were up-regulated, whereas the promotive genes of apoptosis such as ABL2 were down-regulated. Among oncogene/tumors suppressors, SKY was down-regulated. Some genes such as Integrin beta 8, Integrin beta 7, DNA-PK, CSPCP, byglycan, Tenacin and DNA Topo were up-regulated. A number of genes, including LAR, MEK1, eps15, TDGF1, ARHGDIA were down-regulated. In general, expression of the cancer progression genes was up-regulated, while expression of anti-cancer progression genes was down-regulated. These differentially expressed genes tested with RT-PCR were in consistent with cDNA array findings.
CONCLUSION: Investigation of these genes in HCC is helpful in disclosing molecular mechanism of pathogenesis and progression of HCC. For the first time few genes were discovered in HCC. Further study is required for the precise relationship between the altered genes and their correlation with the pathogenesis of HCC.

Ono R, Taki T, Taketani T, et al.
LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23).
Cancer Res. 2002; 62(14):4075-80 [PubMed] Related Publications
There are a limited number of reports of acute myeloid leukemia (AML) with t(10;11)(q22;q23). We showed that the MLL gene on 11q23 was fused to the LCX (leukemia-associated protein with a CXXC domain) gene on 10q22 in a de novoadult AML-M2 with trilineage dysplasia having t(10;11)(q22;q23). LCX consisted of at least 12 exons and was predicted to encode a 2136-amino-acid protein with an estimated molecular mass of 235.3 kDa. The LCX protein had a zinc-binding CXXC domain that MLL also contains within a methyltransferase domain, three nuclear localization signals, an alpha-helical coiled-coil region, and two homologous regions to CG2083 proteins of Drosophila melanogaster. We found approximately 12-, 9.5-, and 7.5-kb transcripts of LCX. Expression of the 7.5-kb transcript was detected in fetal heart, lung, and brain, and in adult skeletal muscle, thymus, and ovary. Expression of the 9.5-kb transcript was detected in fetal lung and brain and in adult ovary. Expression of the 12-kb transcript was detected in fetal heart and brain and in adult thymus and ovary. LCX was expressed in 8 of 22 leukemic cell lines, but not in EBV-induced normal B-cell lines. The MLL-LCX fusion protein lacked a CXXC domain of LCX, but retained an alpha-helical coiled-coil region at the COOH terminus, similar to MLL-SEPTING, MLL-CDCREL1, MLL-AF1p/Eps15, and MLL-AF6, which suggests that these fusion proteins are involved in the pathogenesis of 11q23-associated leukemia through similar mechanisms.

Waterman H, Yarden Y
Molecular mechanisms underlying endocytosis and sorting of ErbB receptor tyrosine kinases.
FEBS Lett. 2001; 490(3):142-52 [PubMed] Related Publications
The major process that regulates the amplitude and kinetics of signal transduction by tyrosine kinase receptors is endocytic removal of active ligand-receptor complexes from the cell surface, and their subsequent sorting to degradation or to recycling. Using the ErbB family of receptor tyrosine kinases we exemplify the diversity of the down regulation process, and concentrate on two sorting steps whose molecular details are emerging. These are the Eps15-mediated sorting to clathrin-coated regions of the plasma membrane and the c-Cbl-mediated targeting of receptors to lysosomal degradation. Like in yeast cells, sorting involves not only protein phosphorylation but also conjugation of ubiquitin molecules. The involvement of other molecules is reviewed and recent observations that challenge the negative regulatory role of endocytosis are described. Finally, we discuss the relevance of receptor down regulation to cancer therapy.

So CW, So CK, Cheung N, et al.
The interaction between EEN and Abi-1, two MLL fusion partners, and synaptojanin and dynamin: implications for leukaemogenesis.
Leukemia. 2000; 14(4):594-601 [PubMed] Related Publications
The mixed lineage leukaemia gene, MLL (also called HRX, ALL-1) in acute leukaemia is fused to at least 16 identified partner genes that display diverse structural and biochemical properties. Using GST pull down and the yeast two hybrid system, we show that two different MLL fusion partners with SH3 domains, EEN and Abi-1, interact with dynamin and synaptojanin, both of which are involved in endocytosis. Synaptojanin, a member of the inositol phosphatase family that has recently been shown to regulate cell proliferation and survival, is also known to bind to Eps15, the mouse homologue of AF1p, another fusion partner of MLL. Expression studies show that synaptojanin is strongly expressed in bone marrow and immature leukaemic cell lines, very weakly in peripheral blood leukocytes and absent in Raji, a mature B cell line. We found that the SH3 domains of EEN and Abi-1 interact with different proline-rich domains of synaptojanin while the EH domains of Eps15 interact with the NPF motifs of synaptojanin. In vitro competitive binding assays demonstrate that EEN displays stronger binding affinity than Abi-1 and may compete with it for synaptojanin. These findings suggest a potential link between MLL fusion-mediated leukaemogenesis and the inositol-signalling pathway.

Pohl U, Smith JS, Tachibana I, et al.
EHD2, EHD3, and EHD4 encode novel members of a highly conserved family of EH domain-containing proteins.
Genomics. 2000; 63(2):255-62 [PubMed] Related Publications
Exon trapping from a bacterial artificial chromosome (BAC 78138) mapping to the 19q13.3 glioma tumor suppressor candidate region yielded two exons that recognized a 3.6-kb transcript on Northern blot. Screening of a human fetal brain cDNA library with these exons identified three novel genes, designated EHD2, EHD3, and EHD4, which are homologous to the recently characterized human EHD1 (testilin/HPAST) and its mouse homolog Ehd1, as well as to homologs in Drosophila (Past1) and Caenorhabditis elegans. Alignment of the predicted peptide sequences revealed striking similarities, with multiple conserved regions that include a nucleotide-binding consensus site at the N-terminus, a bipartite nuclear localization signal, and an eps15 homology (EH) protein-binding domain with an EF-hand motif at the C-terminus. The genes are specifically expressed, with EHD2 highly expressed in heart, EHD3 in brain and heart, and EHD4 in heart and pancreas. EHD2 was confirmed to originate from BAC 78138 at 19q13.3; radiation hybrid mapping localized EHD3 and EHD4 to 2p21 and 15q11.1, respectively; EHD1 has been previously mapped to 11q13. The three EHD1 paralogs therefore represent novel members of a family of human EH domain-containing proteins that may play a role in endocytosis and signaling. Mutation analysis of the five coding exons of EHD2 in gliomas failed to detect any tumor-specific alterations, thus indicating that EHD2 is an unlikely candidate for the 19q tumor suppressor gene.

Rogaia D, Grignani F, Carbone R, et al.
The localization of the HRX/ALL1 protein to specific nuclear subdomains is altered by fusion with its eps15 translocation partner.
Cancer Res. 1997; 57(5):799-802 [PubMed] Related Publications
Translocations involving the HRX/ALL1 locus at chromosomal region 11q23 are among the most frequent cytogenetic abnormalities in acute leukemias. 11q23 translocations involve different chromosome partners and lead to the formation of HRX/ALL1 fusion proteins. The HRX/ALL1 protein is a putative transcription factor that has been implicated in developmental regulation in mammals. We report here the cellular localization of the HRX/ALL1 protein as well as that of the HRX/ALL1-eps15 fusion protein, the result of the t(1;11) (p32-q23) translocation of acute myeloid leukemias. The HRX/ALL1 protein was localized to both the cytoplasm and the nucleus. The nuclear pattern was characterized by diffuse staining, perinuclear accumulation, and localization within nuclear bodies of variable size, morphology, and number. The HRX/ALL1-eps15 localized exclusively to the nucleus within bodies that were smaller and more numerous than the HRX/ALL1 nuclear bodies. HRX/ALL1 fusion with an unknown partner in leukemia blasts with 11q23 abnormalities had similar morphological features. Thus, the fusion with eps15 alters the cellular compartmentalization of HRX/ALL1, providing a putative mechanism for activation of HRX/ALL1 by 11q23 abnormalities.

Alvarez CV, Shon KJ, Miloso M, Beguinot L
Structural requirements of the epidermal growth factor receptor for tyrosine phosphorylation of eps8 and eps15, substrates lacking Src SH2 homology domains.
J Biol Chem. 1995; 270(27):16271-6 [PubMed] Related Publications
Phosphorylation of two newly identified epidermal growth factor (EGF) receptor substrates, eps8 and eps15, which do not possess Src homology (SH2) domains, was investigated using EGF receptor mutants of the autophosphorylation sites and deletion mutants of the carboxyl-terminal region. Two mutants, F5, in which all five tyrosine autophosphorylation sites substituted by phenylalanine, and Dc 123F, in which four tyrosines were removed by deletion and the fifth (Tyr-992) was mutated into phenylalanine, phosphorylated eps8 and eps15 as efficiently as the wild-type receptor. In contrast, SH2-containing substrates, phospholipase C gamma, the GTPase-activating protein of Ras, the p85 subunit of phosphatidylinositol 3 kinase, and the Src and collagen homology protein, are not phosphorylated by the F5 and Dc 123F mutants. A longer EGF receptor deletion mutant, Dc 214, lacking all five autophosphorylation sites, was unable to phosphorylate eps15 but phosphorylated eps8 13-fold more than the wild-type receptor. To determine the EGF receptor region important for phosphorylation of eps8 and eps15, progressive deletion mutants lacking the final 123, 165, 196, and 214 COOH-terminal residues were used. eps8 phosphorylation was progressively increased in Dc 165, Dc 196, and Dc 214 EGF receptor mutants, indicating that removal of the final 214 COOH-terminal residues increases the phosphorylation of this substrate by the EGF receptor. In contrast, eps15 was phosphorylated by Dc 123 and Dc 165 EGF receptor mutants but not by Dc 196 and Dc 214 mutants. This indicates that a region of 30 residues located between Dc 165 and Dc 196 is essential for eps15 phosphorylation. This is the first demonstration of structural requirements in the EGF receptor COOH terminus for efficient phosphorylation of non-SH2-containing substrates. In addition, enhanced eps8 phosphorylation correlates well with the increased transforming potential of EGF receptor deletion mutants Dc 196 and Dc 214, suggesting that this substrate may be involved in mitogenic signaling.

Bernard OA, Mauchauffe M, Mecucci C, et al.
A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL.
Oncogene. 1994; 9(4):1039-45 [PubMed] Related Publications
Most of the translocations affecting the chromosome band 11q23, frequently seen in human acute leukemias, involve a restricted area of the HRX gene. We have characterized two t(1;11)(p32;q11) translocations which fuse the HRX gene to a novel gene, AF-1p on chromosome 1p32, in two myeloid leukemias. The der (11) chromosome expresses the 1368 N-terminal amino acids of HRX, including the AT-hook, snRNP and methyltransferase similarities, fused to almost all the AF-1p product. The predicted wild type AF-1p product is a 98 kDa acidic protein which does not exhibit similarity to the AF-4, AF-9 and ENL gene products. It is highly similar to the murine eps 15 gene product, which encodes a cytoplasmic phosphoprotein. Our data indicate that AF-1p defines another class of genes fused to HRX in 11q23 abnormalities.

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Cite this page: Cotterill SJ. EPS15 gene, Cancer Genetics Web: http://www.cancer-genetics.org/EPS15.htm Accessed:

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