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

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Integrin receptor binding to extracellular matrix proteins generates intracellular signals via enhanced tyrosine phosphorylation events that are important for cell growth, survival, and migration. This review will focus on the functions of the focal adhesion kinase (FAK) protein-tyrosine kinase (PTK) and its role in linking integrin receptors to intracellular signaling pathways. FAK associates with several different signaling proteins such as Src-family PTKs, p130Cas, Shc, Grb2, PI 3-kinase, and paxillin. This enables FAK to function within a network of integrin-stimulated signaling pathways leading to the activation of targets such as the ERK and JNK/mitogen-activated protein kinase pathways. Focus will be placed on the structural domains and sites of FAK tyrosine phosphorylation important for FAK-mediated signaling events and how these sites are conserved in the FAK-related PTK, Pyk2. We will review what is known about FAK activation by integrin receptor-mediated events and also non-integrin stimuli. In addition, we discuss the emergence of a consensus FAK substrate phosphorylation sequence. Emphasis will also be placed on the role of FAK in generating cell survival signals and the cleavage of FAK during caspase-mediated apoptosis. An in-depth discussion will be presented of integrin-stimulated signaling events occurring in the FAK knockout fibroblasts (FAK-) and how these cells exhibit deficits in cell migration. FAK re-expression in the FAK- cells confirms the role of this PTK in the regulation of cell morphology and in promoting cell migration events. In addition, these results reinforce the potential role for FAK in promoting an invasive phenotype in human tumors.
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PMID:Signaling through focal adhesion kinase. 1035 9

Activation of heregulin (HRG) signaling has been implicated in the development of aggressive phenotype in breast cancer cells. The mechanisms through which HRG regulates the progression of breast cancer cells to a more invasive or motile phenotype are currently unknown. Because the process of cell migration must involve dynamic changes in the formation of new focal adhesions at the leading edge and dissolution of preexisting focal points, we explored the potential HRG regulation of paxillin, a major component of focal adhesion. Here, we report that HRG stimulation of noninvasive breast cancer MCF-7 cells resulted in the up-regulation of paxillin mRNA and protein. The observed HRG stimulation of paxillin mRNA expression was completely blocked by actinomycin D (a transcriptional inhibitor) as well as by cycloheximide (a protein synthesis inhibitor), suggesting the involvement of an inducible protein factor(s) and transcriptional regulation of paxillin mRNA by HRG. Extension of these observations to other HRG-responsive human cell lines also demonstrated that HRG has a significant capacity to up-regulate the paxillin expression. Furthermore, the levels of paxillin expression were closely linked with the coexpression of human epidermal growth factor receptor 2 (HER2)/HER3 receptors in breast cancer cell lines and in grade III human breast tumors. This study is the first demonstration of regulation of paxillin expression by a polypeptide growth factor, and it suggests a potential role for paxillin in the HER2 pathway in breast cancer.
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PMID:Transcriptional up-regulation of paxillin expression by heregulin in human breast cancer cells. 1038 44

Activin A and Transforming Growth Factor-beta (TGF-beta) are members of a common family of cytokines that bind to and stimulate serine/threonine kinase receptors. Activin A and TGF-beta are important during embryonic development exerting both positive and negative effects on cell growth. In the adult organism, they function in processes such as tissue repair, cellular proliferation, and differentiation. Although activin A and TGF-beta often induce opposite functional outcomes in specific cells; proliferation or differentiation, both were found to stimulate the formation of actin stress fibers and focal adhesions in serum-starved rat aortic smooth muscle (RASM) cells. These structural changes were accompanied by phosphorylation of the focal adhesion proteins, paxillin, and p130(cas). Similar cytoskeletal and biochemical changes were observed with the vasoactive agonist angiotensin II. Activation of the ERK/MAP kinase pathway has been implicated in the migration in certain cell types. However, while activin A, TGF-beta, and angiotensin II all stimulated ERK activity in RASM cells, only activin A and angiotensin II stimulated migration. TGF-beta failed to illicit a chemotactic response. Furthermore, pharmacologic inhibition of MEK activity failed to block migration in response to activin A and angiotensin II, indicating RASM migration can occur independent of ERK activity. These results suggest that TGF-beta and activin A share several signaling pathways with angiotensin II leading to cytoskeletal remodeling and ERK activation, but there are distinct differences regarding the effect of these agonists on cellular migration.
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PMID:Activin A and TGF-beta stimulate phosphorylation of focal adhesion proteins and cytoskeletal reorganization in rat aortic smooth muscle cells. 1043 85

LPS directly disrupts EC barrier function in vitro and in vivo. This barrier dysfunction has been reported to occur in EC derived from both the macro- and microvasculature of varying species, including humans. Unlike other EC responses, LPS-induced loss of endothelial barrier function is protein-synthesis independent. In fact, protein synthesis inhibition enhances the LPS effect. The lipid A moiety is responsible for LPS-induced activation of the non-CD14-bearing EC, and agents that bind to and neutralize this highly conserved portion of the LPS molecule can crossprotect against EC barrier dysfunction elicited by LPS derived from diverse species of Gram-negative bacteria. Although the presentation of LPS to CD14-bearing cells such as macrophages and monocytes has been well characterized, far less is known about the interactions of LPS with the non-CD14-bearing EC. An EC receptor involved in LPS binding and cellular activation has yet to be identified. The presence of the accessory molecules, LBP and sCD14, are prerequisite to LPS-induced activation of EC at clinically relevant LPS concentrations. As with monocytes and macrophages, the CD14 dependence of LPS-induced endothelial barrier dysfunction can be overcome with high concentrations of LPS. In the absence of LBP and sCD14, a 200,000-fold increase in LPS concentration is required to elicit the same increments in EC monolayer permeability relative to when these accessory molecules are present. Within 30 minutes after LPS exposure, PTK activation is observed. PTK inhibition blocks LPS-induced EC actin depolymerization and endothelial barrier dysfunction which are seen only after a > or = 2-hour stimulus-to-response lag time. Furthermore this LPS-induced actin depolymerization is a prerequisite to opening up the paracellular pathway and loss of monolayer integrity. Interestingly LPS-induced increments in transendothelial 14C-BSA flux and EC detachment parallel caspase-mediated cleavage of ZA and FA proteins that participate in cell-cell and cell-matrix adhesion. The cleavage of the ZA components, beta- and gamma-catenin, does not affect their ability to bind the transmembrane protein, cadherin, or the actin-binding protein, alpha-catenin, suggesting that the linkage of the ZA to the actin cytoskeleton remains intact. LPS-induced cleavage of the FA protein, FAK, leads to dissociation of its catalytic domain from paxillin substrate and decreased paxillin phosphotyrosine content. Caspase inhibition protects against LPS-provoked apoptosis, cleavage of adherens junction proteins, paxillin dephosphorylation, cell-shape changes, and EC detachment. In contrast it fails to block LPS-induced increments in transendothelial 14C-BSA flux. PTK inhibition, which does protect against increased transendothelial 14C-BSA flux, does not block LPS-induced proteolytic cleavage events and only partially inhibits EC detachment. These findings suggest that the EC detachment and endothelial barrier dysfunction elicited by LPS are mediated through distinct pathways (Fig. 6). Much of the work to date has focused on LPS interactions with mCD14-bearing cells, such as monocytes and macrophages, which are central to the inflammatory response elicited by endotoxin. EC, which line the vasculature, are one of the first host tissue barriers to encounter circulating LPS. Because damage to the endothelium is known to contribute to the development of multiorgan failure, including ARDS, understanding LPS-induced EC dysfunction in the setting of Gram-negative septicemia has clear pathophysiologic implications. (ABSTRACT TRUNCATED)
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PMID:Direct effects of endotoxin on the endothelium: barrier function and injury. 1053 83

Vascular endothelial growth factor (VEGF) is a principal regulator of vasculogenesis and angiogenesis. VEGF expresses its effects by binding to two VEGF receptors, Flt-1 and KDR. However, properties of Flt-1 and KDR in the signal transduction of VEGF-mediated effects in endothelial cells (ECs) were not entirely clarified. We investigated this issue by using two newly developed blocking monoclonal antibodies (mAbs) against Flt-1 and KDR. VEGF elicits DNA synthesis and cell migration of human umbilical vein endothelial cells (HUVECs). The pattern of inhibition of these effects by two mAbs indicates that DNA synthesis is preferentially mediated by KDR. In contrast, the regulation of cell migration by VEGF appears to be more complicated. Flt-1 regulates cell migration through modulating actin reorganization, which is essential for cell motility. A distinct signal is generated by KDR, which influences cell migration by regulating cell adhesion via the assembly of vinculin in focal adhesion plaque and tyrosine-phosphorylation of focal adhesion kinase (FAK) and paxillin.
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PMID:Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells. 1081 5

Differentiation of PC12 cells triggered by nerve growth factor (NGF) is characterized by several well-defined events including induction of a set of neuron-specific genes, gain of membrane excitability, and morphological changes such as neurite outgrowth. Here we report that K252a, a protein kinase inhibitor, converts the proliferation signal of epidermal growth factor (EGF) into the morphological differentiation signal without inducing the sustained activation of ERK and the expression of neurofilament. Major effects of EGF/K252a, found also in the NGF-treated cells, are the sustained mobility shift of paxillin in SDS-PAGE and the promoted association of Crk-II with paxillin. These effects explain the prominent and robust development of peripheral focal adhesion assembly and stress fiber-like structures observed in the early stages of PC12 cell differentiation. These results suggest a model that cytoskeletal reorganization via focal adhesion assembly triggered by NGF provides a signal required for the morphological differentiation of PC12 cells.
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PMID:Sustained formation of focal adhesions with paxillin in morphological differentiation of PC12 cells. 1085 Jun 58

The properties of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF in human umbilical vein endothelial cells (HUVECs) were investigated by using two newly developed blocking monoclonal antibodies (mAbs) against Flt-1 and KDR. VEGF stimulated the expression of transcription factor Ets-1 as well as matrix metalloproteinase-1 (MMP-1) and Flt-1 in HUVECs. The KDR/Flt-1 heterodimer and the KDR homodimer mediate the expression of Ets-1, MMP-1, and Flt-1. VEGF also stimulated DNA synthesis and migration of HUVECs. DNA synthesis is mediated by the same signaling system as the expression of Ets-1. In contrast, cell migration is regulated by two distinct signaling systems. The Flt-1 homodimer is required for actin reorganization. The KDR/Flt-1 heterodimer and the KDR homodimer are required for the assembly of vinculin in focal adhesion plaque by regulating the phosphorylation of focal adhesion kinase (FAK) and paxillin.
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PMID:Properties of two VEGF receptors, Flt-1 and KDR, in signal transduction. 1086 39

We recently described germline and somatic mutations in the MET gene associated with papillary renal carcinoma type 1. MET mutation M1268T was located in a codon highly conserved among receptor tyrosine kinases, and homologous to the codon mutated in multiple endocrine neoplasia type 2B, and many cases of sporadic medullary carcinoma of the thyroid gland (Ret M918T). Ret M918T and MET M1268T have previously been shown to be highly active in mouse NIH3T3 transformation assays, and to change the substrate specificity of the kinase. We studied the mechanism of transformation mediated by MET M1268T by analysing a clone, F4, derived from NIH3T3 cells transformed by MET M1268T. In contrast to NIH3T3 cells, F4 cells grew in suspension in tissue culture, and rapidly formed tumors in nude mice. We found that c-Src was constitutively bound to MET proteins in F4 cells, and that Src kinase activity was elevated. Transfection of dominant negative Src constructs into F4 cells eliminated the ability of F4 cells to grow in suspension culture and retarded the growth of F4 cells in vivo. The ability of transfected dominant negative Src constructs to inhibit the growth of F4 cells correlated with the inhibition of phosphorylation of paxillin and focal adhesion kinase. Transfection of dominant negative Src constructs into F4 cells had no effect on Grb2 binding or PLC gamma phosphorylation. The results suggest that c-Src participates in the tumorigenic phenotype induced in NIH3T3 cells by MET M1268T by signaling through focal adhesion kinase and paxillin. Oncogene (2000).
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PMID:Tumorigenesis mediated by MET mutant M1268T is inhibited by dominant-negative Src. 1087 51

Hyaluronic acid (HA), a nonsulfated glycosaminoglycan, regulates cell adhesion and migration. Small HA fragments (3-25 disaccharide units) induce neovascularization. We investigated the effect of HA and a HA fragment (10-15 disaccharide units, F1) on primary human endothelial cells (ECs). Human pulmonary ECs (HPAEC) and lung microvessel ECs (HMVEC-L) bound HA (K(d) approximately 1 and 2.3 nm, respectively) and expressed 17,780 and 16,690 HA binding sites, respectively. Both ECs showed HA-mediated cell adhesion; however, HMVEC-L was 1.5-fold better. Human umbilical vein ECs neither bound HA nor showed HA-mediated adhesion. All three ECs expressed CD44 ( approximately 110 kDa). The expression of receptor for HA-mediated motility (RHAMM) (approximately 80 kDa) was the highest in HMVEC-L, followed by HPAEC and human umbilical vein ECs. RHAMM, not CD44, bound HA in all three ECs. F1 was better than HA and stimulated a 2. 5- and 1.8-fold mitogenic response in HMVEC-L and HPAEC, respectively. Both HA and F1 induced tyrosine phosphorylation of p125(FAK), paxillin, and p42/44 ERK in HMVEC-L and HPAEC, which was blocked by an anti-RHAMM antibody. These results demonstrate that RHAMM is the functional HA receptor in primary human ECs. Heterogeneity exists among primary human ECs of different vascular origins, with respect to functional HA receptor expression and function.
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PMID:Differences in hyaluronic acid-mediated functions and signaling in arterial, microvessel, and vein-derived human endothelial cells. 1088 22

The non-receptor tyrosine kinase PYK2 appears to function at a point of convergence of integrins and certain G protein-coupled receptor (GPCR) signaling cascades. In this study, we provide evidence that translocation of PYK2 to focal adhesions is triggered both by cell adhesion to extracellular matrix proteins and by activation of the histamine GPCR. By using different mutants of PYK2 as green fluorescent fusion proteins, we show that the translocation of PYK2 to focal adhesions is not dependent on its catalytic activity but rather is mediated by its carboxyl-terminal domain. Translocation of PYK2 to focal adhesions was attributed to enhanced tyrosine phosphorylation of PYK2 and its association with the focal adhesion proteins paxillin and p130(Cas). Translocation of PYK2 to focal adhesions, as well as its tyrosine phosphorylation in response to histamine treatment, was abolished in the presence of protein kinase C inhibitors or cytochalasin D treatment, whereas activation of protein kinase C by phorbol ester resulted in focal adhesion targeting of PYK2 and its tyrosine phosphorylation in an integrin-clustering dependent manner. Overexpression of a wild-type PYK2 enhanced ERK activation in response to histamine, whereas a kinase-deficient mutant substantially inhibited this response. Furthermore, inhibition of PYK2 translocation to focal adhesions abolished ERK activation in response to histamine treatment. These results suggest that PYK2 apparently links between GPCRs and focal adhesion-dependent ERK activation and can provide the molecular basis underlying PYK2 function at a point of convergence between signaling pathways triggered by extracellular matrix proteins and certain GPCR agonists.
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PMID:Targeting of PYK2 to focal adhesions as a cellular mechanism for convergence between integrins and G protein-coupled receptor signaling cascades. 1091 88


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