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Query: EC:2.7.10.2 (
focal adhesion kinase
)
44,029
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Paxillin is a focal adhesion adapter protein involved in the integration of growth factor- and adhesion-mediated signal transduction pathways. Paxillin LD motifs have been demonstrated to bind to several proteins associated with remodeling of the actin cytoskeleton including the
focal adhesion kinase
, vinculin, and a complex of proteins comprising p95PKL, PIX, and PAK (Turner, C.E., M. C. Brown, J.A. Perrotta, M.C. Riedy, S.N. Nikolopoulos, A.R. McDonald, S. Bagrodia, S. Thomas, and P.S. Leventhal. 1999. J. Cell Biol. 145:851-863). In this study, we report the cloning and initial characterization of a new paxillin LD motif-binding protein,
actopaxin
. Analysis of the deduced amino acid sequence of
actopaxin
reveals a 42-kD protein with two calponin homology domains and a paxillin-binding subdomain (PBS). Western blotting identifies
actopaxin
as a widely expressed protein. Actopaxin binds directly to both F-actin and paxillin LD1 and LD4 motifs. It exhibits robust focal adhesion localization in several cultured cell types but is not found along the length of the associated actin-rich stress fibers. Similar to paxillin, it is absent from actin-rich cell-cell adherens junctions. Also,
actopaxin
colocalizes with paxillin to rudimentary focal complexes at the leading edge of migrating cells. An
actopaxin
PBS mutant incapable of binding paxillin in vitro cannot target to focal adhesions when expressed in fibroblasts. In addition, ectopic expression of the PBS mutant and/or the COOH terminus of
actopaxin
in HeLa cells resulted in substantial reduction in adhesion to collagen. Together, these results suggest an important role for
actopaxin
in integrin-dependent remodeling of the actin cytoskeleton during cell motility and cell adhesion.
...
PMID:Actopaxin, a new focal adhesion protein that binds paxillin LD motifs and actin and regulates cell adhesion. 1113 73
Paxillin is a focal adhesion adapter protein involved in integrin signaling. Paxillin LD motifs bind several focal adhesion proteins including the
focal adhesion kinase
, vinculin, the Arf-GTPase-activating protein paxillin-kinase linker, and the newly identified actin-binding protein
actopaxin
. Microsequencing of peptides derived from a 50-kDa paxillin LD1 motif-binding protein revealed 100% identity with integrin-linked kinase (ILK)-1, a serine/threonine kinase that has been implicated in integrin, growth factor, and Wnt signaling pathways. Cloning of ILK from rat smooth muscle cells generated a cDNA that exhibited 99.6% identity at the amino acid level with human ILK-1. A monoclonal antibody raised against a region of the carboxyl terminus of ILK, which is identical in rat and human ILK-1 protein, recognized a 50-kDa protein in all cultured cells and tissues examined. Binding experiments showed that ILK binds directly to the paxillin LD1 motif in vitro. Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ILK occurs in vivo in both adherent cells and cells in suspension. Immunofluorescence microscopy of fibroblasts demonstrated that endogenous ILK as well as transfected green fluorescent protein-ILK co-localizes with paxillin in focal adhesions. Analysis of the deduced amino acid sequence of ILK identified a paxillin-binding subdomain in the carboxyl terminus of ILK. In contrast to wild-type ILK, paxillin-binding subdomain mutants of ILK were unable to bind to the paxillin LD1 motif in vitro and failed to localize to focal adhesions. Thus, paxillin binding is necessary for efficient focal adhesion targeting of ILK and may therefore impact the role of ILK in integrin-mediated signal transduction events.
...
PMID:Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions. 1130 46
Cell survival depends on proper propagation of protective signals through intracellular signaling intermediates. We report here that calponin homology domain-containing integrin-linked kinase (ILK)-binding protein (
CH-ILKBP
), a widely expressed adaptor protein localized at plasma membrane-actin junctions, is essential for transmission of survival signals. Cells that are depleted of
CH-ILKBP
undergo extensive apoptosis despite the presence of cell-extracellular matrix contacts and soluble growth factors. The activating phosphorylation of protein kinase B (
PKB
/Akt), a key regulator of apoptosis, is impaired in the absence of
CH-ILKBP
. Importantly, loss of
CH-ILKBP
prevents the membrane translocation of
PKB
/Akt. Furthermore, forced membrane targeting of
PKB
/Akt bypasses the requirement of
CH-ILKBP
for the activating phosphorylation of
PKB
/Akt, suggesting that
CH-ILKBP
is required for the membrane translocation but not the subsequent phosphorylation of
PKB
/Akt. Finally, we show that loss of
CH-ILKBP
is also required for the full activation of extracellular signal-regulated kinase (ERK)1/2. However, restoration of the
PKB
/Akt activation is sufficient for protection of cells from apoptosis induced by the depletion of
CH-ILKBP
despite the persistent suppression of the ERK1/2 activation. Thus,
CH-ILKBP
is an important component of the prosurvival signaling pathway functioning primarily by facilitating the membrane translocation of
PKB
/Akt and consequently the activation of
PKB
/Akt in response to extracellular survival signals.
...
PMID:CH-ILKBP regulates cell survival by facilitating the membrane translocation of protein kinase B/Akt. 1265 98
Cell attachment and the assembly of cytoskeletal and signaling complexes downstream of integrins are intimately linked and coordinated. Although many intracellular proteins have been implicated in these processes, a new paradigm is emerging from biochemical and genetic studies that implicates integrin-linked kinase (ILK) and its interacting proteins, such as
CH-ILKBP
(alpha-parvin), paxillin, and PINCH in coupling integrins to the actin cytoskeleton and signaling complexes. Genetic studies in Drosophila, Caenorhabditis elegans, and mice point to an essential role of ILK as an adaptor protein in mediating integrin-dependent cell attachment and cytoskeletal organization. Here we demonstrate, using several different approaches, that inhibiting ILK kinase activity, or expression, results in the inhibition of cell attachment, cell migration, F-actin organization, and the specific cytoskeletal localization of
CH-ILKBP
and paxillin in human cells. We also demonstrate that the kinase activity of ILK is elevated in the cytoskeletal fraction and that the interaction of
CH-ILKBP
with ILK within the cytoskeleton stimulates ILK activity and downstream signaling to
PKB
/Akt and GSK-3. Interestingly, the interaction of
CH-ILKBP
with ILK is regulated by the Pi3 kinase pathway, because inhibition of Pi3 kinase activity by pharmacological inhibitors, or by the tumor suppressor PTEN, inhibits this interaction as well as cell attachment and signaling. These data demonstrate that the kinase and adaptor properties of ILK function together, in a Pi3 kinase-dependent manner, to regulate integrin-mediated cell attachment and signal transduction.
...
PMID:Integration of cell attachment, cytoskeletal localization, and signaling by integrin-linked kinase (ILK), CH-ILKBP, and the tumor suppressor PTEN. 1296 Apr 24
