Paxillin Interactions
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Paxillin Interactions

Signals that derive from cell adhesion to the ECM (Extracellular Matrix) regulate important physiological events including cell motility and growth, and most often involve changes in the organization of the actin cytoskeleton. Cells interact with the ECM via transmembrane receptors, termed integrins, located at the cell surface. Binding of integrins to the ECM is accompanied by a localized clustering of these receptors, with the subsequent recruitment of structural and signaling molecules to the sites of matrix attachment, focal contacts, providing links to the actin cytoskeleton (Ref.1). Numerous proteins present at the cytoplasmic face of FA (Focal Adhesions) include cytoskeletal proteins such as vinculin and talin. In addition, numerous "signaling" proteins with enzymatic activity (e.g., kinases and GTPases) are also components of FA. By clustering these structural and signaling components together, integrins transduce the signals required to mediate certain aspects of cell physiology and morphology. These signals include tyrosine phosphorylation of proteins such as Paxillin and p130CAS (Crk-Associated Substrate), activation of protein tyrosine kinases such as the FAK (Focal Adhesion Kinase) and Src and activation of serine/threonine kinases such as the ERKs (Extracellular Signal Regulated Kinases) or Akt/PKB (Protein Kinase-B) pathway mediated by PI3K (Phosphatidylinositol-3 Kinase) (Ref.2).

Paxillin is a multidomain focal contact adapter that localizes with Integrin-Beta1, FAK, Vinculin, and Src family kinases at FA and links integrin signaling with MAPK (Mitogen-Activated Protein Kinase) and p38/JNK (c-Jun N-Terminal Protein Kinase) pathways (Ref.3). It is phosphorylated after cell activation by ECM, Growth factors, Angiotensin-II and neuropeptides, and during embryogenesis, metastasis, and wound repair. The NH2 terminus of Paxillin contains five leucine-rich domains, termed LD motifs (LD1, LD2, LD3, LD4 and LD5), which mediate protein-protein interactions. The LD4 motif of Paxillin binds a complex of proteins implicated in actin cytoskeletal regulation. These include the CDC42 (Cell Division Cycle-42)/RacGEF (Guanine Nucleotide Exchange Factor), PIX (PAK-Interacting Exchange Factor), PAK (p21-Activated Kinase), and the SH2-SH3 adapter protein Nck. This complex is linked to Paxillin through the putative ARF (ADP Ribosylation Factor)-GTPase-activating protein, ARF-GAP and PKL (Paxillin Kinase Linker). PAK also bind directly to Paxillin via the LD4 motif and PKL inhibits ARF1 and ARF6 through this motif. ARF6 activates POR1 (Partner of Rac1) and is associated with lamellipodia formation. Thus, through these associations Paxillin serve as a point of integration in the control of actin cytoskeleton dynamics by both the Rho and ARF family GTPases (Ref.1).

Paxillin localizes to FA through its LIM domains, which are double Zn (Zinc) finger motifs, that function to mediate protein-protein interactions possibly through a direct association with Integrin-Beta tails or an intermediate protein ‘X’. Its primary function is as a molecular adapter or scaffold protein that provides multiple docking sites at the plasma membrane for an array of signaling and structural proteins. For example, it provides a platform for protein tyrosine kinases such as FAK and Src, which are activated as a result of adhesion or growth factor stimulation. Phosphorylation of residues in the N-terminus of Paxillin by these kinases permits the regulated recruitment of downstream effector molecules such as Crk, which (via association with CAS, Crk-Associated Substrate) is important for transduction of external signals into changes in cell motility and for modulation of gene expression by the various MAP Kinase cascades. LIM-domain-associated kinases regulate recruitment of Paxillin to FA. In addition, negative regulators of these pathways, including CSK (C-terminal Src Kinase, an inhibitor of Src activity) and PTP-PEST (a phosphatase that dephosphorylates p130CAS), bind directly to Paxillin, thereby bringing them into close proximity with their targets (Ref.4). Crk connects Paxillin and p130CAS, to downstream signal transducer DOCK180 (Dedicator of Cytokinesis-180) through SH2 and SH3 domains. DOCK180 directly binds to Rac1, a member of the Rho family of small GTPases that regulates and activates the actin cytoskeleton. Crk recruits other signaling molecules such as GEFs, C3G and SOS, to tyrosine-phosphorylated proteins. Tyrosine phosphorylation of Paxillin results in the recruitment of these GEFs to FA that is built on the plasma membrane. C3G and SOS act as upstream regulators for Rap1 and Ras, respectively. These small GTPases are involved in the regulation of MAPK (Ref.5).

Paxillin binds to many proteins involved in effecting changes in the organization of the actin cytoskeleton, which are necessary for cell motility events associated with embryonic development, wound repair and tumor metastasis. These include structural proteins vinculin and actopaxin that bind actin directly to regulators of actin cytoskeletal dynamics such as the ARF-GAP, PKL, the exchange factor PIX and PAK. These proteins serve as modulators/effectors of the ARF and Rho GTPase families (Ref.4). Several of the Paxillin-binding proteins have oncogenic equivalents, such as v-Src, v-Crk and BCR-Abl, which probably use Paxillin both as a substrate and as a docking site to perturb, and even bypass, the normal adhesion and growth factor signaling cascades necessary for controlled cell proliferation. Others, such as the E6 protein from Papillomavirus, facilitate transformation by disrupting the normal links between Paxillin and the actin cytoskeleton by displacing Paxillin-LD-motif-binding proteins (Ref.4).