Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term potentiation (LTP) is an activity-dependent enhancement of synaptic efficacy, considered a model of learning and memory. The biochemical cascade producing LTP requires activation of Src, which upregulates the function of NMDA receptors (NMDARs), but how Src becomes activated is unknown. Here, we show that the focal adhesion kinase CAKbeta/Pyk2 upregulated NMDAR function by activating Src in CA1 hippocampal neurons. Induction of LTP was prevented by blocking CAKbeta/Pyk2, and administering CAKbeta/Pyk2 intracellularly mimicked and occluded LTP. Tyrosine phosphorylation of CAKbeta/Pyk2 and its association with Src was increased by stimulation that produced LTP. Finally, CAKbeta/Pyk2-stimulated enhancement of synaptic AMPA responses was prevented by blocking NMDARS, chelating intracellular Ca(2+), or blocking Src. Thus, activating CAKbeta/Pyk2 is required for inducing LTP and may depend upon downstream activation of Src to upregulate NMDA receptors.
...
PMID:CAKbeta/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus. 1123 21

TFII-I is a transcription factor that shuttles between the cytoplasm and nucleus and is regulated by serine and tyrosine phosphorylation. Tyrosine phosphorylation of TFII-I can be regulated in a signal-dependent manner in various cell types. In B lymphocytes, Bruton's tyrosine kinase has been identified as a TFII-I tyrosine kinase. Here we report that JAK2 can phosphorylate and regulate TFII-I in nonlymphoid cells. The activity of TFII-I on the c-fos promoter in response to serum can be abolished by dominant negative JAK2 or the specific JAK2 kinase inhibitor AG490. Consistent with this, we have also found that JAK2 is activated by serum stimulation of fibroblasts. Tyrosine 248 of TFII-I is phosphorylated in vivo upon serum stimulation or JAK2 overexpression, and mutation of tyrosine 248 to phenylalanine inhibits the ability of JAK2 to phosphorylate TFII-I in vitro. Tyrosine 248 of TFII-I is required for its interaction with and phosphorylation by ERK and its in vivo activity on the c-fos promoter. These results indicate that the interaction between TFII-I and ERK, which is essential for its activity, can be regulated by JAK2 through phosphorylation of TFII-I at tyrosine 248. Thus, like the STAT factors, TFII-I is a direct substrate of JAK2 and a signal-dependent transcription factor that integrates signals from both tyrosine kinase and mitogen-activated protein kinase pathways to regulate transcription.
...
PMID:JAK2 activates TFII-I and regulates its interaction with extracellular signal-regulated kinase. 1131 64

Tyrosine 1062 of Ret, which represents an intracytoplasmic docking site for multiple signaling molecules, is essential for Ret-mediated activation of phosphatidylinositol 3-Kinase (PI3-K). PI3-K, in turn, has been implicated in inducing cell survival and neoplastic transformation mediated by Ret. We have examined the mechanisms by which Ret stimulates PI3-K. Here we show that the Insulin Receptor Substrate-1 (IRS-1) is tyrosine phosphorylated and associated with the p85 regulatory subunit of PI3-K in response to Ret activation. IRS-1 coimmunoprecipitates with Ret and co-expression of IRS-1 results in the potentiation of Ret-mediated activation of Akt(PKB), a bona fide effector of PI3-K. The association with the PTB domain of IRS-1 depends on the phosphorylation of tyrosine 1062 of Ret. The deletion of asparagine 1059 (delN1059) and the substitution of leucine 1061 (L1061P), two Ret mutations identified in families affected by congenital megacolon (Hirschsprung's disease), impair the binding of IRS-1 to Ret as well as Ret-mediated Akt(PKB) stimulation. Finally, we show that Shc, which was previously identified as another ligand of Y1062 of Ret, competes with IRS-1 for the binding to Ret pY1062. All together, these findings suggest that IRS-1 is a component of the signaling pathway which leads to Ret-mediated PI3-K activation, a pathway which can be targeted by Hirschsprung-associated Ret mutations. The alternative binding of Shc and IRS-1 to Ret pY1062 can be a system to modulate the activation of different intracellular signaling pathways and to elicit different biological responses following Ret activation.
...
PMID:The insulin receptor substrate (IRS)-1 recruits phosphatidylinositol 3-kinase to Ret: evidence for a competition between Shc and IRS-1 for the binding to Ret. 1131 48

Protein-tyrosine phosphatase (PTP)-PEST is a cytoplasmic tyrosine phosphatase that can bind and dephosphorylate the focal adhesion-associated proteins p130(CAS) and paxillin. Focal adhesion kinase (FAK) and cell adhesion kinase beta (CAKbeta)/PYK2/CADTK/RAFTK are protein-tyrosine kinases that can colocalize with, bind to, and induce tyrosine phosphorylation of p130(CAS) and paxillin. Thus, we considered the possibility that these kinases might be substrates for PTP-PEST. Using a combination of substrate-trapping assays and overexpression of PTP-PEST in mammalian cells, CAKbeta was found to be a substrate for PTP-PEST. Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST. Dephosphorylation of CAKbeta by PTP-PEST dramatically inhibited CAKbeta kinase activity. In contrast, FAK was a poor substrate for PTP-PEST, and treatment with PTP-PEST had no effect on FAK kinase activity. Tyrosine phosphorylation of paxillin, which is greatly enhanced by CAKbeta overexpression, was dramatically reduced upon coexpression of PTP-PEST. Finally, endogenous PTP-PEST and endogenous CAKbeta were found to localize to similar cellular compartments in epithelial and smooth muscle cells. These results suggest that CAKbeta is a substrate of PTP-PEST and that FAK is a poor PTP-PEST substrate. Further, PTP-PEST can negatively regulate CAKbeta signaling by inhibiting the catalytic activity of the kinase.
...
PMID:Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-PEST-mediated dephosphorylation. 1133 90

Rho, a member of the small GTP-binding proteins, and one of its downstream effectors ROCK (Rho-associated coiled-coil forming protein kinase) play an important role in the invasion of tumor cells. Lysophosphatidic acid (LPA) activates Rho and ROCK and promotes the organization of stress fibers and focal adhesions. However, the effect of LPA on tumor cell invasion is still controversial. In the present study, human osteosarcoma cells treated with a high concentration of LPA (high LPA) showed considerable formation of stress fibers and focal adhesions compared to the cells treated with a low concentration of LPA (low LPA). C3 (inhibitor of Rho) or Y27632 (an inhibitor of ROCK) inhibited the effects of LPA, indicating that LPA activates the Rho-ROCK pathway in the cells. In addition, Rho activation assay showed that the activation level of Rho can be altered by changing the concentration of LPA. Low LPA stimulated the motility and invasion of the cells, while high LPA reduced both. The disruption of extracellular matrix (ECM) by matrix metalloproteinase 2 (MMP2) is also critical for tumor cell invasion. MMP2 is activated by membranous type-1 MMP (MT1-MMP) and type-2 tissue inhibitor of MMP (TIMP2). High LPA suppressed the activation of MMP2 through down-regulation of MT1-MMP and TIMP2. C3 and Y27632 reversed the suppression of the activation of MMP2 and expression of MT1-MMP and TIMP2, suggesting the involvement of the Rho-ROCK pathway in ECM degradation. Tyrosine phosphorylation of focal adhesion kinase (FAK) was also required for the invasion of tumor cells to occur. Low LPA enhanced the tyrosine phosphorylation of FAK whereas high LPA reduced it. In conclusion, we suggest that Rho has a dual effect on the invasion of osteosarcoma cells by modulating the motility, the ability to degrade ECM and tyrosine phosphorylation of FAK.
...
PMID:Small GTP-binding protein, Rho, both increased and decreased cellular motility, activation of matrix metalloproteinase 2 and invasion of human osteosarcoma cells. 1134 66

Carbachol treatment resulted in increased phosphorylation on tyrosine of PKCdelta immunoprecipitated from rat pancreatic acinar cells. The Ca2+-dependent tyrosine kinase PYK2 coimmunoprecipitated with PKCdelta from carbachol-exposed cells and also exhibited increased tyrosine phosphorylation. Tyrosine phosphorylation of both PKCdelta and PYK2 was concentration-dependent with respect to carbachol, and rapid, reaching maximal levels by 5 min of treatment. Exposure of acinar cells to phorbol myristate acetate (PMA), a phorbol ester activator of PKCdelta, also resulted in increased phosphorylation of PKCdelta and PYK2 isolated using anti-PKCdelta immunoprecipitation. These results are suggestive of a physical and functional interaction between PKCdelta and PYK2 following muscarinic stimulation in the pancreatic acinar cell.
...
PMID:Carbachol stimulates TYR phosphorylation and association of PKCdelta and PYK2 in pancreas. 1135 32

alpha-Actinin is tyrosine-phosphorylated in activated human platelets (Izaguirre, G., Aguirre, L., Ji, P., Aneskievich, B., and Haimovich, B. (1999) J. Biol. Chem. 274, 37012--37020). Analysis of platelet RNA by reverse transcription-polymerase chain reaction revealed that alpha-actinin expressed in platelets is identical to the cytoskeletal/non-muscle isoform. A construct of this isoform containing a His(6) tag at the amino terminus was generated. Robust tyrosine phosphorylation of the recombinant protein was detected in cells treated with the tyrosine phosphatase inhibitor vanadate. The tyrosine phosphorylation site was localized to the amino-terminal domain by proteolytic digestion. A recombinant alpha-actinin protein containing a Tyr --> Phe mutation at position 12 (Y12F) was no longer phosphorylated when expressed in vanadate-treated cells, indicating that tyrosine 12 is the site of phosphorylation. The wild type recombinant protein was not phosphorylated in cells lacking the focal adhesion kinase (FAK). Re-expression of FAK in these cells restored alpha-actinin phosphorylation. Purified wild type alpha-actinin, but not the Y12F mutant, was phosphorylated in vitro by wild type as well as a Phe-397 mutant of FAK. In contrast, no phosphorylation was detected in the presence of a kinase-dead FAK. Tyrosine phosphorylation reduced the amount of alpha-actinin that cosedimented with actin filaments. These results establish that alpha-actinin is a direct substrate for FAK and suggest that alpha-actinin mediates FAK-dependent signals that could impact the physical properties of the cytoskeleton.
...
PMID:The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase. 1136 69

During the healing process of skin wounds, human keratinocytes migrate across a provisional matrix of the wound bed. The mechanisms by which keratinocytes migrate on connective tissue are not known. In this study, we examined the role of focal adhesion kinase (FAK), an 125 kDa protein that co-localizes with focal adhesions in cells plated on extracellular matrix. We induced human keratinocytes into various states of migration by plating them on extracellular matrices that minimally, moderately, or strongly induce cellular migration, and then examined the expression of FAK at the protein level and its degree of tyrosine phosphorylation using Western immunoblotting and immunoprecipitation. In highly migratory human keratinocytes, we found that three proteins were predominantly tyrosine phosphorylated, one of them being FAK. Tyrosine phosphorylation of FAK tightly correlated with the level of cellular motility but not cell attachment to the matrix. Time course experiments demonstrated that in highly motile keratinocytes, tyrosine phosphorylation of FAK peaked at 12 h, the time when maximal migration on the matrix ensues. In contrast to FAK, the beta1 integrin subunit of human keratinocytes that configures with the alpha2, alpha3, and alpha5 integrin subunits to form integrin receptors for matrix, did not display tyrosine phosphorylation linked to motility. Using anti-sense oligonucleotides to FAK, we demonstrate that FAK is required for human keratinocyte migration, but not for focal adhesion formation.
...
PMID:Phosphorylation of focal adhesion kinase (pp125(FAK)) is increased in human keratinocytes induced to migrate by extracellular matrices. 1138 19

We previously demonstrated that a recently synthesized drug, TAS-301 [3-bis(4-methoxyphenyl)methylene-2-indolinone], inhibited neointimal thickening after single-balloon injury to the rat common carotid artery by inhibiting both the migration and proliferation processes of vascular smooth muscle cells (VSMCs). The purpose of this current study was to elucidate the possible mechanism of action for its inhibition of the migration process of VSMCs. We also determined the efficacy of TAS-301 on second neointimal formation 14 days after a double-balloon injury to the rat common carotid artery. Neointimal thickening, 14 days after second balloon injury, was reduced by the oral administration of TAS-301 in a dose-dependent manner. In in vitro assays using rat VSMCs, Western blot analysis showed that TAS-301 inhibited platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of both focal adhesion kinase and paxillin. Tyrosine phosphorylation of these proteins depended on the increment of intracellular calcium concentration ([Ca2+]i). The PDGF-induced elevation of [Ca2+]i and activation of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) were also inhibited by TAS-301. Additionally, TAS-301 at 10 micromol/l reduced the extent of F-actin stress fiber depolymerization observed in response to PDGF. These results indicate that TAS-301 reduced the intimal thickening after denudation to a pre-existing lesion to the same extent as it reduced that after a single-balloon injury to the normal artery. Furthermore, the results of our in vitro experiments suggest that antimigratory mechanisms of TAS-301 that contribute to preventing the intimal thickening might be mediated by drug inhibition of Ca2+ -dependent signal molecules and the following cytoskeletal depolymerization.
...
PMID:Tas-301, a new synthetic inhibitor of neointimal thickening after balloon injury, inhibits calcium-dependent signal transduction and cytoskeletal reorganization. 1140 28

The cytoplasmic adaptor protein SLP-65 (BLNK or BASH) is a critical downstream effector of the B cell antigen receptor (BCR). Tyrosine-phosphorylated SLP-65 assembles intracellular signaling complexes such as the Ca(2 +) initiation complex encompassing phospholipase C-gamma2 and Bruton's tyrosine kinase. It is, however, unclear how the SLP-65 signaling module can be recruited to the plasma membrane. Here we show that following B cell stimulation, SLP-65 associates directly with the BCR signaling subunit, the Ig-alpha / Ig-beta heterodimer. The interaction is mediated by the Src homology 2 domain of SLP-65 and the phosphorylated Ig-alpha tyrosine 204, which is located outside of the immunoreceptor tyrosine-based activation motif. Our data identify an unexpected BCR phosphorylation pattern and indicate that Ig-alpha has the capability to serve as transmembrane adaptor in BCR signaling.
...
PMID:Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha. 1144 66


<< Previous 1 2 3 4 5 6 7 8 9 10

---