Abstract
Protein p130Cas constitutes an adaptor protein mainly involved in integrin signaling downstream of Src kinase. Owing to its modular structure, p130Cas acts as a general regulator of cancer cell growth and invasiveness induced by different oncogenes. However, other mechanisms of p130Cas signaling leading to malignant progression are poorly understood. Here, we show a novel interaction of p130Cas with Ser/Thr kinase PKN3, which is implicated in prostate and breast cancer growth downstream of phosphoinositide 3‐kinase. This direct interaction is mediated by the p130Cas SH3 domain and the centrally located PKN3 polyproline sequence. PKN3 is the first identified Ser/Thr kinase to bind and phosphorylate p130Cas and to colocalize with p130Cas in cell structures that have a pro‐invasive function. Moreover, the PKN3–p130Cas interaction is important for mouse embryonic fibroblast growth and invasiveness independent of Src transformation, indicating a mechanism distinct from that previously characterized for p130Cas. Together, our results suggest that the PKN3–p130Cas complex represents an attractive therapeutic target in late‐stage malignancies.
Highlights
The structure of p130Cas consists of an N-terminal SRC homology 3 (SH3) domain, substrate domain (SD), and serine-rich domain (SRD) followed by Src and phosphoinositide 3-kinase (PI3K) binding regions and terminated by a CAS-family C-terminal homology domain (CCH) (Cabodi, del Pilar Camacho-Leal, et al, 2010)
Association of p130Cas via the p130Cas SH3 domain with FAK and Src at focal adhesions transmits signals that induce lamellipodia and cell migration, support cell proliferation and cell invasiveness, and block anoikis (Donato et al, 2010; Tazaki et al, 2008; Ruest et al, 2001; Nikonova et al, 2014; Defilippi et al, 2006; Brábek et al, 2005). p130Cas has been shown to be phosphorylated at serine residues, which correlates with an invasive cell phenotype and is partially dependent on the p130Cas SH3 domain; responsible serine/threonine kinases have not yet been identified (Makkinje et al, 2009)
Src activity was slightly increased by PKN3 expression in a p130Cas-dependent manner, which is consistent with a recent study demonstrating that PKN3 could promote Src activity in osteoclasts (Fig. S4, A and B) (Uehara et al, 2017). These results indicated that PKN3 regulates the growth of mouse embryonic fibroblasts (MEFs) and that this effect requires PKN3-p130Cas interaction independently of p130Cas SRD domain phosphorylation
Summary
The structure of p130Cas consists of an N-terminal SRC homology 3 (SH3) domain, substrate domain (SD), and serine-rich domain (SRD) followed by Src and PI3K binding regions and terminated by a CAS-family C-terminal homology domain (CCH) (Cabodi, del Pilar Camacho-Leal, et al, 2010). The level of p130Cas tyrosine phosphorylation is mainly dependent on the binding capacity of its SH3 domain, which facilitates direct interaction of p130Cas with the polyproline motif of various phosphatases (e.g., PTP1B, PTP-PEST) and kinases (FAK, PYK2) or mediates indirect association with Src via a FAK (PYK2) bridge (Fonseca et al, 2004; Ruest et al, 2001; Astier et al, 1997). Association of p130Cas via the p130Cas SH3 domain with FAK and Src at focal adhesions transmits signals that induce lamellipodia and cell migration, support cell proliferation and cell invasiveness, and block anoikis (Donato et al, 2010; Tazaki et al, 2008; Ruest et al, 2001; Nikonova et al, 2014; Defilippi et al, 2006; Brábek et al, 2005). P130Cas has been shown to interact with 14-3-3 proteins in a phosphoserine-dependent manner, which occurs mainly at lamellipodia during integrinmediated cell attachment to the extracellular matrix (ECM) (Garcia-Guzman et al, 1999)
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