Paxillin Regulates Androgen- and Epidermal Growth Factor-induced MAPK Signaling and Cell Proliferation in Prostate Cancer Cells

Abstract

2 Genomic actions involve binding of androgens to ARs, which then translocate to the nucleus, bind to androgen-response elements, and alter gene expression. In contrast, ARs also induce rapid nongenomic signals that are generally mediated by cross-talk between the AR and either G-proteins or growth factor receptors (1-4). Although transcriptional effects of androgens have been extensively studied, mechanisms regulating nongenomic actions of androgens are poorly understood.One potential regulator of nongenomic androgen actions is paxillin. Paxillin is a multidomain adaptor protein that integrates many signals from integrins, cell surface receptors, and growth factors (10, 11). Through these interactions, paxillin regulates a variety of physiological functions, including matrix organization, cell motility, tissue remodeling, metastasis, gene expression, cell survival, and proliferation (10, 11). Paxillin is comprised of multiple structural domains that modulate protein-protein interactions (10) and numerous serine/threonine and tyrosine phosphorylation targets that act as docking sites for various signaling proteins. Phosphorylation of these sites by growth factor receptor-tyrosine kinases, Src kinases, and serine/threonine kinases regulate adaptor molecule binding that ultimately coordinates complex cell signaling pathways (10). The importance of paxillin in normal physiological functions is further evident from global paxillin knock-out studies, demonstrating that ablation of paxillin in mice is embryonic lethal (12,13).We previously demonstrated that in Xenopus oocytes, paxillin is essential for non-genomic androgen-induced Erk signaling and subsequent Erk-mediated oocyte maturation (5). Specifically, paxillin is required for synthesis and activation of MOS (the germ cell Raf homolog), which then promotes MEK and subsequently Erk signaling (5). Interestingly, Erk-mediated phosphorylation of paxillin is also required for androgen-induced oocyte maturation. Thus, in oocytes, paxillin is both an affector and effector of Erk signaling.Here we significantly extend our findings in Xenopus oocytes to a mammalian somatic system. Given the well defined function of androgens and Erk signaling (3, 6 -8) in prostate cancer

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

“…However, PXN was not found to be an independent predictor due to the small number of samples and follow-up time was not long enough. Several studies have shown that PXN plays an important role in regulating tumor cell proliferation and mediating signal transduction of epidermal growth factor (EGF) (2,(10)(11)(12). Various scholars have also demonstrated that PXN leads to resistance to drugs by inhibiting the apoptosis of cancer cells in non-small cell lung cancer (17).…”

“…Several studies have shown that phosphorylation levels of paxillin (PXN) are related to those of cytokine receptors; the blocking of cell growth factor receptors leads to a compensatory increase in PXN phosphorylation levels, and that PXN plays an important role in mediating signal transduction of the epidermal growth factor (EGF) (2,(10)(11)(12). Therefore, high expression of PXN and increased phosphorylation levels may be one of the reasons for the poor therapeutic effect of cetuximab.…”

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

“…The paxillin homologue leupaxin, a 45 kDa protein with ≈ 37% homology to paxillin, was originally characterized as a multi-functional adaptor protein expressed only in hematopoietic cells [87,[89][90][91]. However, leupaxin, like both Hic-5 and paxillin, has been recently shown to be expressed in a subset of human prostate cancers, accumulating in the nucleus to potentiate androgen receptor (AR) transactivation in a ligand-dependent manner [87,92,93].…”

“…As a possible substitute to HER2, EGFR expression has been documented in 45-70% of TNBCs [169]. Like the HER2 pathway, induction of EGFR by its ligand EGF, has been also been shown to stimulate paxillin serine phosphorylation in a MAPK-dependent manner [170,171].…”

The Adaptor Protein and Arf GTPase-activating Protein Cat-1/Git-1 Is Required for Cellular Transformation

“…This was highlighted by the fact that the mutant form of Cat-1 that is defective in its ability to bind paxillin fails to rescue the block on transformation caused by knocking down endogenous Cat-1 in the HeLa cervical carcinoma cells, whereas the expression of a construct that encodes wild-type Cat-1 and is resistant to RNAi restores transformation. Paxillin has been shown in some cases to be required for the growth of cancer cells and transformed fibroblasts (37,38). These studies together with our own lead to the suggestion that the formation of a Cat-1-paxillin complex might recruit or activate a unique set of signaling proteins that stimulate the growth of transformed cells.…”