Explorer Epidermal Growth Factor Receptor substrate 8 ( Eps 8 ) controls Src / FAK-dependent phenotypes in squamous carcinoma cells

Eps8 is an actin regulatory scaffold protein whose expression is increased in squamous cell carcinoma (SCC) cells. It forms a complex with both focal adhesion kinase (FAK, also known as PTK2) and Src in SCC cells derived from skin carcinomas induced by administration of the chemical DMBA followed by TPA (the DMBA/TPA model). Here, we describe two new roles for Eps8. Firstly, it controls the spatial distribution of active Src in a FAKdependent manner. Specifically, Eps8 participates in, and regulates, a biochemical complex with Src and drives trafficking of Src to autophagic structures that SCC cells use to cope with high levels of active Src when FAK is absent. Secondly, when FAK is expressed in SCC cells, thereby meaning active Src becomes tethered at focal adhesion complexes, Eps8 is also recruited to focal adhesions and is required for FAK-dependent polarization and invasion. Therefore, Eps8 is a crucial mediator of Srcand FAK-regulated processes; it participates in specific biochemical complexes and promotes actin re-arrangements that determine the spatial localization of Src, and modulates the functions of Src and FAK during invasive migration.

[1]  C. Petit,et al.  EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness , 2014, Orphanet Journal of Rare Diseases.

[2]  Steve D. M. Brown,et al.  The Actin-Binding Proteins Eps8 and Gelsolin Have Complementary Roles in Regulating the Growth and Stability of Mechanosensory Hair Bundles of Mammalian Cochlear Outer Hair Cells , 2014, PloS one.

[3]  J. Heath,et al.  Novel Binding Partners and Differentially Regulated Phosphorylation Sites Clarify Eps8 as a Multi-Functional Adaptor , 2013, PloS one.

[4]  J. Heath,et al.  Regulation of fibroblast growth factor receptor signalling and trafficking by Src and Eps8 , 2013, Journal of Cell Science.

[5]  Mu-Kuan Chen,et al.  Expression of Eps8 correlates with poor survival in oral squamous cell carcinoma , 2012, Asia-Pacific journal of clinical oncology.

[6]  S. Wilkinson,et al.  Src‐dependent autophagic degradation of Ret in FAK‐signalling‐defective cancer cells , 2012, EMBO reports.

[7]  V. Brunton,et al.  The role of focal adhesion kinase catalytic activity on the proliferation and migration of squamous cell carcinoma cells , 2012, International journal of cancer.

[8]  E. Formstecher,et al.  Ezrin regulates microvillus morphogenesis by promoting distinct activities of Eps8 proteins , 2012, Molecular biology of the cell.

[9]  Owen J. Sansom,et al.  Autophagic targeting of Src promotes cancer cell survival following reduced FAK signalling , 2011, Nature Cell Biology.

[10]  T. Svitkina,et al.  The signaling adaptor Eps8 is an essential actin capping protein for dendritic cell migration. , 2011, Immunity.

[11]  Valeria Zampini,et al.  Eps8 Regulates Hair Bundle Length and Functional Maturation of Mammalian Auditory Hair Cells , 2011, PLoS biology.

[12]  U. Manor,et al.  Regulation of Stereocilia Length by Myosin XVa and Whirlin Depends on the Actin-Regulatory Protein Eps8 , 2011, Current Biology.

[13]  M. Eck,et al.  The FERM domain: organizing the structure and function of FAK , 2010, Nature Reviews Molecular Cell Biology.

[14]  A. Cuervo,et al.  Eps8 is recruited to lysosomes and subjected to chaperone-mediated autophagy in cancer cells. , 2010, Experimental cell research.

[15]  M. Maa,et al.  The interplay between Eps8 and IRSp53 contributes to Src-mediated transformation , 2010, Oncogene.

[16]  K. Anderson,et al.  A Complex between FAK, RACK1, and PDE4D5 Controls Spreading Initiation and Cancer Cell Polarity , 2010, Current Biology.

[17]  N. Volkmann,et al.  Molecular Basis for the Dual Function of Eps8 on Actin Dynamics: Bundling and Capping , 2010, PLoS biology.

[18]  G. Thomas,et al.  Upregulation of Eps8 in oral squamous cell carcinoma promotes cell migration and invasion through integrin-dependent Rac1 activation , 2009, Oncogene.

[19]  Petros Koumoutsakos,et al.  TScratch: a novel and simple software tool for automated analysis of monolayer wound healing assays. , 2009, BioTechniques.

[20]  Yun-Ju Chen,et al.  Eps8 decreases chemosensitivity and affects survival of cervical cancer patients , 2008, Molecular Cancer Therapeutics.

[21]  T. Giese,et al.  Eps8 is increased in pancreatic cancer and required for dynamic actin-based cell protrusions and intercellular cytoskeletal organization. , 2007, Cancer letters.

[22]  Gareth E. Jones,et al.  Focal adhesion kinase controls actin assembly via a FERM-mediated interaction with the Arp2/3 complex , 2007, Nature Cell Biology.

[23]  Yun-Ju Chen,et al.  EPS8 Facilitates Cellular Growth and Motility of Colon Cancer Cells by Increasing the Expression and Activity of Focal Adhesion Kinase* , 2007, Journal of Biological Chemistry.

[24]  Andrea Disanza,et al.  Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8–IRSp53 complex , 2006, Nature Cell Biology.

[25]  F. Cordelières,et al.  A guided tour into subcellular colocalization analysis in light microscopy , 2006, Journal of microscopy.

[26]  G. Scita,et al.  Palladin binds to Eps8 and enhances the formation of dorsal ruffles and podosomes in vascular smooth muscle cells , 2006, Journal of Cell Science.

[27]  Min Zhang,et al.  Blebbistatin, a novel inhibitor of myosin II ATPase activity, increases aqueous humor outflow facility in perfused enucleated porcine eyes. , 2005, Investigative ophthalmology & visual science.

[28]  S. Grant,et al.  Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. , 2004, Genes & development.

[29]  Ping Chen,et al.  Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. , 2004, Journal of medicinal chemistry.

[30]  C. Tacchetti,et al.  A novel actin barbed-end-capping activity in EPS-8 regulates apical morphogenesis in intestinal cells of Caenorhabditis elegans , 2004, Nature Cell Biology.

[31]  Andrea Disanza,et al.  Eps8 controls actin-based motility by capping the barbed ends of actin filaments , 2004, Nature Cell Biology.

[32]  H. Yeh,et al.  Participation of p97Eps8 in Src-mediated Transformation* , 2004, Journal of Biological Chemistry.

[33]  Timothy J Mitchison,et al.  Dissecting Temporal and Spatial Control of Cytokinesis with a Myosin II Inhibitor , 2003, Science.

[34]  G. Scita,et al.  Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1 , 2003, The Journal of cell biology.

[35]  Pier Paolo Di Fiore,et al.  The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5 , 2000, Nature.

[36]  E. Parkinson,et al.  Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells , 1999, Oncogene.

[37]  C. Betsholtz,et al.  EPS8 and E3B1 transduce signals from Ras to Rac , 1999, Nature.

[38]  M. Maa,et al.  Enhancement of tyrosyl phosphorylation and protein expression of eps8 by v-Src. , 1999, Biochimica et biophysica acta.

[39]  J. Parsons,et al.  p130Cas, a Substrate Associated with v-Src and v-Crk, Localizes to Focal Adhesions and Binds to Focal Adhesion Kinase* , 1996, The Journal of Biological Chemistry.

[40]  L. Minichiello,et al.  Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF‐dependent mitogenic signals. , 1993, The EMBO journal.

[41]  A. Balmain,et al.  Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis , 1986, Nature.

[42]  J. Yates,et al.  Isolation of focal adhesion proteins for biochemical and proteomic analysis. , 2012, Methods in molecular biology.

[43]  W. A. Yeudall,et al.  Role for EPS8 in squamous carcinogenesis. , 2009, Carcinogenesis.

[44]  M. Maa,et al.  Overexpression of p97Eps8 leads to cellular transformation: implication of pleckstrin homology domain in p97Eps8-mediated ERK activation , 2001, Oncogene.