Members of the Zyxin Family of LIM Proteins Interact with Members of the p130Cas Family of Signal Transducers

Abstract

Integrin binding to extracellular matrix proteins induces formation of signaling complexes at focal adhesions. Zyxin co-localizes with integrins at sites of cellsubstratum adhesion and is postulated to serve as a docking site for the assembly of multimeric protein complexes involved in regulating cell motility. Recently, we identified a new member of the zyxin family called TRIP6. TRIP6 is localized at focal adhesions and overexpression of TRIP6 slows cell migration. In an effort to define the molecular mechanism by which TRIP6 affects cell migration, the yeast two-hybrid assay was employed to identify proteins that directly bind to TRIP6. This assay revealed that both TRIP6 and zyxin interact with CasL/HEF1, a member of the Cas family. This association is mediated by the LIM region of the zyxin family members and the SH2 domain-binding region of CasL/ HEF1. Furthermore, the association between p130 Cas and the two zyxin family members was demonstrated to occur in vivo by co-immunoprecipitation. Zyxin and Cas family members may cooperate to regulate cell motility.Integrin-mediated cell adhesion to extracellular matrix (ECM) 1 components is crucial for many cell activities including cell survival, proliferation, migration, and differentiation (1-5). Upon binding to the substratum, integrins recruit many cytoskeletal components to the sites of cell adhesion and establish a structural link between the elements of the ECM and actin filaments. In addition to contributing to the physical link between the extracellular and intracellular environments, integrin engagement also regulates several signaling pathways (2, 6, 7). Although the cytoplasmic domains of integrins do not exhibit any enzymatic activity, they can activate intracellular signaling pathways by recruiting a number of signaling proteins to focal adhesions (8 -10).Recent studies have identified a number of proteins that participate in integrin-dependent signaling pathways (10 -13). These signaling molecules include non-receptor tyrosine kinases (14, 15), serine/threonine kinases (7, 16 -18), a lipid kinase (19), protein-tyrosine phosphatases (20 -24), and small GTPases in the Ras and Rho families (25-29). In addition to proteins that harbor catalytic domains, integrins recruit several adaptor proteins that facilitate the assembly of multicomponent signaling complexes (30 -32). For instance, upon substratum adhesion, the adaptor protein p130 Cas (p130 Crk-associated substrate ) is recruited to integrin-rich sites where it docks several regulatory molecules including Src, Crk, and FAK (focal adhesion kinase) (33-35).Members of the zyxin family have also been postulated to function in integrin-mediated signaling (36). Zyxin, the founding member of the family, is a phosphoprotein that is localized at focal adhesions and along actin filaments (37, 38). The protein displays an NH 2 -terminal proline-rich region, one or more leucine-rich nuclear export signals (depending on the species) and three copies of the LIM motif at its COOH terminus (Fig. 1A) (36, 39, 4...

Deregulation of HEF1 Impairs M-Phase Progression by Disrupting the RhoA Activation Cycle

“…Like HEF1, zyxin transits from focal adhesion to the mitotic spindle in mitosis (Hirota et al, 2000). Zyxin and HEF1 have been shown to physically interact (Yi et al, 2002). Finally, in a recent study of the consequences of zyxin depletion, the most noticeable phenotype was the loss of stress fibers; stress fibers are under the control of RhoA (Ridley and Hall, 1992).…”

Stac3 Is Required for Myotube Formation and Myogenic Differentiation in Vertebrate Skeletal Muscle

“…The deletion of 8 amino acid residues of zebrafish lamin A resulted in embryonic senescence and S-phase accumulation/ arrest (39). TRIP6 (thyroid receptor-interacting protein 6), a member of the zyxin family of proteins, functions to relay signals from the cell surface to the nucleus to weaken adherin junctions and promote actin cytoskeletal reorganization and cell migration (40). NCKIPSD encodes NCK interacting protein with the SH3 domain (SPIN90).…”

Integrin signalling adaptors: not only figurants in the cancer story

“…p130CAS has also emerged as a pro-invasive molecule. To regulate invasion p130CAS associates with the ZYXIN family members (ZYXIN, AJUBA, also known as JUB, and thyroid hormone receptor interactor 6 (TRIP6) [56][57][58] and the transcription factor zinc finger protein 384 (ZNF384, also known as CIZ or NMP4) 56 . These interactions lead to transcription of matrix metalloproteinase genes required for the invasive program 59 .…”