EPS15 (Kr.1p32.3), AF1P, MLLt5, (EGF - EGFR signalointitiehen kuuluva proteiini

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846373/

Suomeksi:
 EPS15, esiintyy Klathriinipitoisissa kalvokuopissa ja  osallistuu reseptorivälitteisen EGF:n  - endosytoosiin.  Se on endosyyttinen adaptori ja assosioituu myös ESCRT-0 kompleksin jäseniin  HRS ja STAM.  Sitä ubikitinoi CUL3- SPOPL, mikä johtaa EPS15:n  johtaa hajoitukseen.  Jos SPOPL puuttuu,  EPS15 kertyy ja akkumuloituu  HRS:n kanssa.  Tutkijat päätyivät huomioon, että CUL3-SPOPL E3 ubikitiiniligaasikompleksi säätelee endosyyttistä liikennöintiä ja multivesikulaaristen kappaleiden (MVB) muodostusta  ubikitinoimalla ja hajoittamalla EPS15 endosomeissa- ja täten mm vaikuttaa influenssa A-virusinfektiota ja EGFR- hajoamista ja muiden EPS15 kohteiden hajoamista.

• Abstract. Cullin-3 (CUL3)-based ubiquitin ligases regulate endosome maturation and trafficking of endocytic cargo to lysosomes in mammalian cells. Here, we report that these functions depend on SPOPL, a substrate-specific CUL3 adaptor. We find that SPOPL associates with endosomes and is required for both the formation of multivesicular bodies (MVBs) and the endocytic host cell entry of influenza A virus. In SPOPL-depleted cells, endosomes are enlarged and fail to acquire intraluminal vesicles (ILVs). We identify a critical substrate ubiquitinated by CUL3-SPOPL as EPS15, an endocytic adaptor that also associates with the ESCRT-0 complex members HRS and STAM on endosomes. Indeed, EPS15 is ubiquitinated in a SPOPL-dependent manner, and accumulates with HRS in cells lacking SPOPL. Together, our data indicates that a CUL3-SPOPL E3 ubiquitin ligase complex regulates endocytic trafficking and MVB formation by ubiquitinating and degrading EPS15 at endosomes, thereby influencing influenza A virus infection as well as degradation of EGFR and other EPS15 targets.

DOI: http://dx.doi.org/10.7554/eLife.13841.001
Hakemalla netistä löytää kuvia, joisa on teorioita EPS15:n  vaikutusmekanismista. ja  EGFR-reseptorin endosomaalisesta kierrosta. Aktivoitunutreseptori  joutuu multivesikulaaristen rakkuloiden tielle ja sitten lopulta lysosomiin hajoamaan,  muta  inaktivoituneet reseptorit hyödynnetään uudestgaan ja  ne  palautuvat  plasmakalvoon kiertävässä endosomissa.
Osittain EGFR ilmenee kaveola-alueessa ja  vapautuu  aktivaatiosta.
Fosforyloitunut EGFR ubikitinoituu ja joutuu EPS15 vaikutuksen alaisuuteen joko klatriinivälitteisellä  tai klatriinsita riippumattomalla kulkureitiollä.
 EPS15 assosioituu ubikitinoituneeseen EGF-reseptoriin UIM- domeenillaan ja  klatriinipeiteisen rakkulan  AP-2 kompleksin alfa-adaptiinilla.
EPS15 havaitaan  siten  varhaisessa endosomissa ternaarisessa kompleksissa ECRT-0-tekijöiden STAM ja HRS kanssa- ne ovat  sitoutuneena klatriiniin.  Aktiivina olleet  reseptorit pakataan multivesikulaarisiin rakkuloihin(MVB) ESCRT-0,-I,-II ja _III kompleksien avulla ja lopulta hajoitetaan lysosomissa.

• Lisäteitoa tästä EPS15-tekijästä, jolla on täten  yhteyksiä  ESCRT_ järjestelmäänkin

Geeni EPS15 (Kr. 1p32.3), AF1P, MLLT5

https://www.ncbi.nlm.nih.gov/gene/2060 
 AF1P; AF-1P; MLLT5

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]

Expression Ubiquitous expression in brain (RPKM 29.8), testis (RPKM 29.2) and 25 other tissues See more Orthologs mouse all

Related articles in PubMed

1. Over-expression of EPS15 is a favorable prognostic factor in breast cancer. Dai X, et al. Mol Biosyst, 2015 Nov. PMID 26289382
2. UIM domain-dependent recruitment of the endocytic adaptor protein Eps15 to ubiquitin-enriched endosomes. Gucwa AL, et al. BMC Cell Biol, 2014 Sep 27. PMID 25260758, Free PMC Article  Eps15 is an endocytic adaptor protein that stimulates clathrin-mediated endocytosis. Among other interactions, Eps15 binds ubiquitin via UIM domains, recruiting ubiquitinated cargo into clathrin-coated vesicles. In EGF-treated cells, Eps15 also localizes to endosomes. The basis of this localization is not known. We show for the first time that ubiquitin is sufficient for Eps15 recruitment to endosomes. We speculate that Eps15 recruitment to ubiquitin-rich endosomes may reduce the level of Eps15 at the plasma membrane, slowing endocytosis to allow time for processing of ubiquitinated cargo in endosomes.
3. Molecular characterization of identical, novel MLL-EPS15 translocation and individual genomic copy number alterations in monozygotic infant twins with acute lymphoblastic leukemia. Kotecha RS, et al. Haematologica, 2012 Sep. PMID 22581003, Free PMC Article  The t(1;11) (MLL-EPS15) translocation is rare with only a small number of clinical cases published and three reports of molecular characterization at the transcriptional level.^5–7 The epidermal growth factor receptor pathway substrate 15 (EPS15) gene encodes a protein that is involved in receptor-mediated endocytosis of epidermal growth factor. We present an MLL-EPS15 rearrangement with novel breakpoints at the transcriptional and DNA level in monozygotic infant twins with ALL and characterization of the molecular changes in their leukemic cells. The methods are described in the Online Supplementary Appendix. Both twins were diagnosed at seven weeks of age, with a peripheral blood blast population of 99.96×10⁹/L in Twin One and 154.87×10⁹/L in Twin Two. CD19⁺, CD24⁺, CD10⁻, B-precursor ALL was confirmed on immunophenotyping. Banded chromosomal analysis revealed a 46,XX,t(1;11)(p32;q23)[13]/46,XX[7] karyotype in Twin One and a 46,XX,t(1;11) (p32;q23)[8]/ibid+X[4]/46,XX[8] karyotype in Twin Two, with fluorescence in situ hybridization confirming MLL involvement.⁸
4. Role of receptor-mediated endocytosis in the formation of vaccinia virus extracellular enveloped particles. Husain M, et al. J Virol, 2005 Apr. PMID 15767409, Free PMC Article
5. A ubiquitin-interacting motif (UIM) is essential for Eps15 and Eps15R ubiquitination. Klapisz E, et al. J Biol Chem, 2002 Aug 23. PMID 12072436

See all (139) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. Fcho1/2Eps15/RAP-2 ternary complexes to facilitate conformational activation of AP-2 by the Fcho1/2 interdomain linker to promote AP-2 cargo engagement.
2. An interaction of Eps15 and pS227-FIP2 at the appropriate time and location in polarizing cells is necessary for proper establishment of epithelial polarity.
3. RAB11FIP3 combines with Eps15 homology domain 1 to promote the endocytosis recycling of phosphorylation of epithelial growth factor receptor.
4. Together, the data indicate that a CUL3-SPOPL E3 ubiquitin ligase complex regulates endocytic trafficking and formation of multivesicular bodies by ubiquitinating and degrading EPS15 at endosomes.
5.   https://www.ncbi.nlm.nih.gov/pubmed/26748853  (2016  identify USP9X as a novel regulator of EGFR endocytosi  Following activation by its cognate ligand(s), the epidermal growth factor receptor (EGFR) is rapidly routed to the lysosome for degradation in a ubiquitination-dependent fashion. This pathway represents the major mechanism of long-term attenuation of EGFR signaling, and its deregulation is a significant feature in different types of cancers. Here we demonstrate, through a systematic RNAi-based approach, that several deubiquitinating (DUB) enzymes extend or decrease EGFR half-life upon EGF stimulation. We focus on USP9X, whose depletion severely affects EGFR turnover, interfering with its internalization and trafficking. We identify the endocytic protein Eps15 as one of the critical substrates of USP9X, and we map the Eps15 ubiquitination sites. We found that Eps15 monoubiquitination occurs already at minimal dose of EGF stimulation and is essential for EGFR internalization. Overall, our findings identify USP9X as a novel regulator of EGFR endocytosis and suggest a model whereby cycles of ubiquitination and deubiquitination events on endocytic accessory proteins may regulate the internalization and trafficking of the EGFR toward the lysosomes.
6. over-expression of EPS15 is a potential favorable prognostic marker in breast cancer.
7. MLL-EPS15 translocation and individual genomic copy number alterations in monozygotic infant twins are associated with acute lymphoblastic leukemia.
8. Ubiquitin is sufficient for Eps15 recruitment to endosomes.
9. Results indicate that phosphorylation of epidermal growth factor receptor pathway substrate 15 (Eps15) at Ser-796 is catalyzed by p38 directly.
10. distinct forms of Eps15 direct EGFR to either the late endosome/lysosome for degradation (Eps15) or to the recycling endosome for transit back to the cell surface (Eps15S)

Submit: New GeneRIF Correction See all GeneRIFs

FIGURE 8.

J Biol Chem. 2011 Oct 7; 286(40): 35196–35208.

Published online 2011 Aug 8. doi:  10.1074/jbc.M111.247577

Model depicting roles of three Eps15 forms in EGFR trafficking. Eps15 functions in internalization of EGFR at the plasma membrane, and Eps15b localized on early endosomes mediates sorting of EGFR to the late endosome/lysosome for degradation. Eps15S directs the internalized EGFR to the recycling endosome for recycling back to the cell surface.