Abstract
ABSTRACTEps8 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 FAK-dependent 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 Src- and 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.
Highlights
Epidermal growth factor receptor kinase substrate 8 (Eps8) was originally identified as a substrate for receptor tyrosine kinases, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and ErbB-2 (Fazioli et al, 1993)
This is because we previously found that: (1) Eps8 is hugely upregulated in squamous cell carcinoma (SCC) cells derived from skin carcinomas induced by administration of the chemicals 7,12-dimethylbenz(a)anthracene (DMBA) followed by 12-O-tetradecanoylphorbol-13-acetate) (TPA) [the DMBA/TPA model; driven by mutated oncogenic H-Ras (Quintanilla et al, 1986)] when compared to normal keratinocytes and in human SCCs, and (2) it associates with both FAK and active Src in SCC cells
Eps8 expression is increased in SCC cells We found that Eps8 expression was elevated in SCC cells derived from the DMBA/TPA model of chemical carcinogenesis (SCC 1 and SCC 2 cells; Fig. 1A) when compared to primary keratinocytes isolated from mouse tails
Summary
Epidermal growth factor receptor kinase substrate 8 (Eps8) was originally identified as a substrate for receptor tyrosine kinases, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and ErbB-2 (Fazioli et al, 1993). Eps is a direct binding partner and phosphorylation target of the Src non-receptor tyrosine kinase (Cunningham et al, 2013; Maa et al, 1999). Eps consists of an N-terminal phosphotyrosine-binding (PTB) domain, an SH3 domain and a C-terminal effector domain, through which Eps is thought to direct actin regulatory functions, such as capping barbed ends and promoting bundling (Disanza et al, 2004; Disanza et al, 2006; Hertzog et al, 2010). The role of Eps on stimulation of the Rac signaling pathway is mediated by the formation of a tri-complex consisting of Eps, Abi-1 and Sos-1 (Innocenti et al, 2003; Scita et al, 1999)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
