Paxillin comes of age

Abstract

Paxillin is a multi-domain scaffold protein that localizes to the intracellular surface of sites of cell adhesion to the extracellular matrix. Through the interactions of its multiple protein-binding modules, many of which are regulated by phosphorylation, paxillin serves as a platform for the recruitment of numerous regulatory and structural proteins that together control the dynamic changes in cell adhesion, cytoskeletal reorganization and gene expression that are necessary for cell migration and survival. In particular, paxillin plays a central role in coordinating the spatial and temporal action of the Rho family of small GTPases, which regulate the actin cytoskeleton, by recruiting an array of GTPase activator, suppressor and effector proteins to cell adhesions. When paxillin was first described 18 years ago, the amazing complexity of cell-adhesion organization, dynamics and signaling was yet to be realized. Herein we highlight our current understanding of how the multiple protein interactions of paxillin contribute to the coordination of celladhesion function. Biologists 2008Biologists doi:10.1242 Journal of Cell Science 2436 regulated interactions with multiple structural and signaling molecules, serves as a nexus for the control of the Rho family of GTPases in their capacity as essential regulators of the actin cytoarchitecture and adhesion dynamics. The importance of emerging microscopy technologies and model systems for elucidating paxillin function and directing future avenues of investigation will also be discussed. Paxillin structure and the paxillin ʻinteractomeʼThe molecular cloning of paxillin and subsequent peptide-sequence analysis revealed that it comprises numerous discrete structural domains (Brown et al., 1996;Turner and Miller, 1994) that have since been identified as protein-binding modules (Brown and Turner, 2004;Turner, 2000). In turn, this has led to the current classification of paxillin as a molecular adaptor or scaffold protein, the primary function of which is to serve as a nexus to coordinate, integrate and facilitate efficient cell signaling, through direct and indirect interactions with multiple signaling and structural proteins that constitute the paxillin 'interactome'.The C-terminal half of paxillin contains four LIM (Lin11, Isl-1, Mec-3) domains, which are double-zinc-finger motifs that mediate protein-protein interactions (Perez-Alvarado et al., 1994;Schmeichel and Beckerle, 1994) and are found in all eukaryotes but are absent from prokaryotes (Kadrmas and Beckerle, 2004). The LIM2 and LIM3 domains of paxillin are essential for targeting the protein to focal adhesions (Brown et al., 1996). It has been established that phosphorylation of these domains contributes to the regulation of focal-adhesion targeting of paxillin (Brown et al., 1998b), but the identity of the docking protein for paxillin has so far remained elusive, despite the fact that the localization of paxillin at focal adhesions is an absolute requirement for most paxillinmediated processes. The LIM domain...

Prognostic significance and function of phosphorylated ribosomal protein S6 in esophageal squamous cell carcinoma

“…We found that S6 or S6K1 depletion led to pronounced inhibition of focal adhesion formation as revealed by less densely stained paxillin, which mediates the interaction between the actin cytoskeleton and integrins (Figures 4c and d). 20,21 Thus, these data suggest that S6K1-S6 signaling is critical to focal adhesion formation, which is essential for esophageal cancer cell motility. To explore the molecular mechanism underlying S6-mediated focal adhesion and invasion, we examined the status of signaling pathways that mediate cell motility.…”

B4GALNT3 Expression Predicts a Favorable Prognosis and Suppresses Cell Migration and Invasion via β1 Integrin Signaling in Neuroblastoma

“…28 The FAK-Src complex binds to and phosphorylates various adaptor proteins, including paxillin, which serves as a platform for the recruitment of numerous proteins that together control the cytoskeletal reorganization and gene expression that are necessary for cell migration and survival. 29 Activated FAK-Src complex in many tumor cells generates signals leading to tumor growth and metastasis. 28 Moreover, the paxillin-ERK complex plays a role in cell survival and motility.…”

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

“…This apparent cooperation between the two structural domains of paxillin can also be seen in the localization and activation of the non-receptor tyrosine kinase, FAK. Failure of FAK to bind paxillin has been shown to result in decreased FAK focal adhesion localization and tyrosine phosphorylation [51,52,66,108]. Characterization of the paxillin-FAK interaction shows that it is the C-terminal focal adhesion targeting domain of FAK, specifically the paxillin binding sequences 1 and 2 (PBS 1 and 2) within this domain, that are capable of binding both the second and the fourth LD motifs of paxillin with equal affinity [51,108].…”

“…Failure of FAK to bind paxillin has been shown to result in decreased FAK focal adhesion localization and tyrosine phosphorylation [51,52,66,108]. Characterization of the paxillin-FAK interaction shows that it is the C-terminal focal adhesion targeting domain of FAK, specifically the paxillin binding sequences 1 and 2 (PBS 1 and 2) within this domain, that are capable of binding both the second and the fourth LD motifs of paxillin with equal affinity [51,108]. Together, the differential phosphorylation of the paxillin LIM motifs 2 and 3, is believed to facilitate the subcellular localization of FAK to focal adhesions [51,108].…”

“…The inducible nature of these protein-interaction domains confers paxillin with an additional level of regulation with respect to the spatial and temporal associations it makes with SH2-containing binding partners like the adaptor protein Crk [66]. Crk has been shown to bind directly to a SH2 site generated by pY31 and pY118 of paxillin which in turn, recruits the guanine nucleotide exchange factor DOCK180 and affects the overall state of cellular polarization and migration through the activation of the Rho GTPase, Rac1 [66,86,108,114,115]. Other SH2-containing proteins that have been identified to bind directly to tyrosine phosphorylated paxillin include: the p85 subunit of PI3K with pY31, pY40 and pY118 and p120RasGAP with pY31 and PY118 [66,86,116].…”