Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progenitor cells in the mammalian forebrain can undergo either symmetric or asymmetric cell divisions by varying their cleavage orientation. In asymmetric divisions, cells distribute apically and basally localized proteins differentially to their daughters. Here we explore the intrinsic polarity of neuroepithelial cells in the developing telencephalon. Actin microfilaments are concentrated apically, forming beltlike structures that encircle spots of gamma-tubulin immunoreactivity. Staining for N-cadherin, beta-catenin, and the tyrosine kinase substrates pp120 and paxillin is also enriched at the lumenal surface, presumably due to the localization of these proteins at adherens junctions. Phosphotyrosine immunoreactivity is concentrated apically in rings, suggesting that adherens junctions are enriched for signaling molecules. In mitotic cells it appears that adherens junction proteins and phosphotyrosine immunoreactivity may be inherited either symmetrically or asymmetrically, depending on the cell's cleavage orientation during mitosis. The differential inheritance of junctional proteins may determine whether a daughter cell can respond to extrinsic signals after mitosis.
Mol Cell Neurosci 1998 Jul
PMID:Intrinsic polarity of mammalian neuroepithelial cells. 967 50

Vascular endothelial cells are important in a variety of physiological and pathophysiological processes. The growth and functions of vascular endothelial cells are regulated both by soluble mitogenic and differentiation factors and by interactions with the extracellular matrix; however, relatively little is known about the role of the matrix. In the present study, we investigate whether integrin-mediated anchorage to a substratum coated with the extracellular matrix protein fibronectin regulates growth factor signaling events in human endothelial cells. We show that cell adhesion to fibronectin and growth factor stimulation trigger distinct initial tyrosine phosphorylation events in endothelial cells. Thus, integrin-dependent adhesion of endothelial cells leads to tyrosine phosphorylation of both focal adhesion kinase and paxillin, but not of several growth factor receptors. Conversely, EGF stimulation causes receptor autophosphorylation, with no effect on focal adhesion kinase or paxillin tyrosine phosphorylation. Adhesion to fibronectin, in the absence of growth factors, leads to activation of MAPK. In addition, adhesion to fibronectin also potentiates growth factor signaling to MAPK. Thus, polypeptide growth factor activation of MAPK in anchored cells is far more effective than in cells maintained in suspension. Other agonists known to activate MAPK were also examined for their ability to activate MAPK in an anchorage-dependent manner. The neuropeptide bombesin, the bioactive lipid lysophosphatidic acid (LPA), and the cytokine tumor necrosis factor alpha, which signal through diverse mechanisms, were all able to activate MAPK to a much greater degree in fibronectin-adherent cells than in suspended cells. In addition, tumor necrosis factor alpha activation of c-Jun kinase (JNK) was also much more robust in anchored cells. Together, these data suggest a cooperation between integrins and soluble mitogens in efficient propagation of signals to downstream kinases. This cooperation may contribute to anchorage dependence of mitogenic cell cycle progression.
Mol Biol Cell 1998 Aug
PMID:Integrin-mediated signaling events in human endothelial cells. 969 60

The ubiquitously expressed Na-H exchanger NHE1 functions in regulating intracellular pH and cell volume. NHE1 activity is stimulated by hormones, growth factors, and activation of integrin receptors. We recently determined that NHE1 activity is also stimulated by activation of the low molecular weight GTPase RhoA and that increases in NHE1 activity are necessary for RhoA-induced formation of actin stress fibers. We now show that NHE1 acts downstream of RhoA to modulate initial steps in integrin signaling for the assembly of focal adhesions. Adhesion of CCL39 fibroblasts on fibronectin was markedly delayed in the presence of the NHE inhibitor ethylisopropylamiloride. In mutant PS120 cells, derived from CCL39 fibroblasts but lacking NHE1, adhesion was also delayed but was rescued in PS120 cells stably expressing NHE1. In the absence of NHE1 activity, cell spreading was inhibited, and the accumulation of integrins, paxillin, and vinculin at focal contacts was impaired. Additionally, tyrosine phosphorylation of p125(FAK) induced by integrin clustering was also impaired. Inactivation of RhoA with C3 transferase and inhibition of the Rho-kinase p160ROCK with the pyridine derivative Y-27632 completely abolished activation of NHE1 by integrins but not by platelet-derived growth factor. These findings indicate that NHE1 acts downstream of RhoA to contribute a previously unrecognized critical signal to proximal events in integrin-induced cytoskeletal reorganization.
Mol Biol Cell 1998 Aug
PMID:Na-H exchange acts downstream of RhoA to regulate integrin-induced cell adhesion and spreading. 969 82

Crkl is an adapter protein and phosphotyrosine-containing substrate implicated in transformation by the bcr-abl oncogene and in signaling by cytokines. When phosphorylated, Crkl binds through its Src homology 2 (SH2) domain to other tyrosine phosphoproteins such as paxillin and Cbl. Overexpression of Crkl in fibroblasts induces transformation. Here we examine the role of Crkl in hematopoietic cells and find that overexpression of Crkl confers a signal leading to increased adhesion to fibronectin. In both fibroblasts and hematopoietic cells, individual mutations or deletions of each SH2 and SH3 domain abrogated transformation and adhesion, respectively, indicating that interactions with other proteins such as Cbl and paxillin (SH2 domain) and Abl, Sos, and C3G (N-terminal SH3 domain) are essential for biological activity. In vivo and in vitro tryptic phosphopeptide mapping studies show that Crkl is phosphorylated on multiple tyrosine residues when overexpressed or when activated by Bcr-Abl. Mutation at tyrosine 207, a residue conserved in c-Crk, abrogates all in vivo tyrosine phosphorylation of Crkl. Despite this loss of phosphotyrosine, mutation at this site enhanced Crkl function as measured by complex formation with SH2 binding proteins, signal transduction to Jun Kinase, and fibroblast transformation. These observations implicate Crkl in cellular adhesion and demonstrate that Y207 functions as a negative regulatory site.
Mol Cell Biol 1998 Sep
PMID:Structural requirements for function of the Crkl adapter protein in fibroblasts and hematopoietic cells. 971 May 92

YopH is a protein tyrosine phosphatase (PTP) that is delivered into host mammalian cells via a type III secretion pathway in pathogenic Yersinia species. Although YopH is a highly active PTP, it preferentially targets a subset of tyrosine-phosphorylated proteins in host cells, including p130Cas. Previous in vitro studies have indicated that the carboxy-terminal PTP domain contributes specificity to the interaction of YopH with substrates. However, it is not known if the PTP domain is sufficient for substrate recognition by YopH. Here, we have identified paxillin as an additional substrate of YopH in HeLa cells. In addition, we have identified a domain in the amino-terminal region of YopH that binds to both p130Cas and paxillin and is required for the efficient recognition of substrates by the wild-type enzyme. This 'substrate-binding' domain exhibits a ligand specificity that is similar to that of the Crk Src homology 2 (SH2) domain, and it binds substrates directly in a phosphotyrosine-dependent manner. The substrate-binding domain of YopH may represent a novel type of protein-protein interaction module, as it lacks significant sequence similarity with any known SH2 or phosphotyrosine-binding (PTB) domain.
Mol Microbiol 1998 Sep
PMID:Identification of an amino-terminal substrate-binding domain in the Yersinia tyrosine phosphatase that is required for efficient recognition of focal adhesion targets. 976 93

Insulin can regulate the abundance and organization of filamentous actin within cells in culture. Early studies using cell lines that overexpress the insulin receptor demonstrated that insulin caused a rapid reversible disassembly of actin filaments that coincided with the rapid tyrosine dephosphorylation of focal adhesion kinase. We have extended these studies by demonstrating that paxillin, another focal adhesion protein, and Src undergo tyrosine dephosphorylation in response to insulin in Chinese hamster ovary (CHO) and rat hepatoma (HTC) cells that overexpress the insulin receptor. This contrasted with the effect of insulin in parental CHO and HTC cells in which focal adhesion proteins were not dephosphorylated in response to the hormone. In addition, insulin caused a dispersion of focal adhesion proteins and disruption of actin filament bundles only in cells that overexpressed the insulin receptor. Moreover, in 3T3-L1 adipocytes, which are considered prototypic insulin-responsive cells, actin filament assembly was stimulated, and focal adhesion protein tyrosine phosphorylation was not altered. 3T3-L1 cells have more insulin receptors than either parental CHO or HTC cells but have fivefold less insulin receptors than the overexpressing cell lines. We hypothesize that a threshold may exist in which the overexpression of insulin receptors determines how insulin signaling pathways regulate the actin cytoskeleton.
Mol Biol Cell 1998 Nov
PMID:Opposite effects of insulin on focal adhesion proteins in 3T3-L1 adipocytes and in cells overexpressing the insulin receptor. 980 96

MCF-7 human breast carcinoma cultures grown in the presence of 17-beta estradiol form solid, multicellular nodules, a process that reflects changes in cell-substrate adhesions and loss of growth inhibition. We examined the effects of estradiol on the status of tyrosine phosphorylation in focal adhesion kinase (FAK) and the association of FAK with paxillin using immunoprecipitations and then probing western blots for FAK, phosphotyrosine, and paxillin. Culture of MCF-7 cells for seven days in the presence of 1 nM E2 resulted in decreased tyrosine phosphorylation of FAK compared to controls. The estradiol-induced effect was blocked by 100 nM of the estrogen receptor antagonist 4-hydroxytamoxifen, indicating dephosphorylation of FAK is an estrogen receptor-mediated event. FAK immunoprecipitated from either estradiol or DMSO-treated cells phosphorylated the exogenous substrate poly(Glu,Tyr), suggesting that the potential kinase activity of FAK was not changed by estradiol. Estradiol treatment also resulted in a reduced association between FAK and paxillin. The decreased phosphorylation levels and reduced association between FAK and paxillin may be important steps leading to the loss of stable focal contacts and loss of growth inhibition during MCF-7 nodulation.
J Steroid Biochem Mol Biol 1998 Nov
PMID:Decreased tyrosine phosphorylation of focal adhesion kinase after estradiol treatment of MCF-7 human breast carcinoma cells. 987 83

The coordinated interplay of substrate adhesion and deadhesion is necessary for cell motility. Using MCF-7 cells, we found that insulin-like growth factor I (IGF-I) induces the adhesion of MCF-7 to vitronectin and collagen in a dose- and time-dependent manner, suggesting that IGF-I triggers the activation of different integrins. On the other hand, IGF-I promotes the association of insulin receptor substrate 1 with the focal adhesion kinase (FAK), paxillin, and the tyrosine phosphatase SHP-2, resulting in FAK and paxillin dephosphorylation. Abrogation of SHP-2 catalytic activity with a dominant-negative mutant (SHP2-C>S) abolishes IGF-I-induced FAK dephosphorylation, and cells expressing SHP2-C>S show reduced IGF-I-stimulated chemotaxis compared with either mock- or SHP-2 wild-type-transfected cells. This impairment of cell migration is recovered by reintroduction of a catalytically active SHP-2. Interestingly, SHP-2-C>S cells show a larger number of focal adhesion contacts than wild-type cells, suggesting that SHP-2 activity participates in the integrin deactivation process. Although SHP-2 regulates mitogen-activated protein kinase activity, the mitogen-activated protein kinase kinase inhibitor PD-98059 has only a marginal effect on MCF-7 cell migration. The role of SHP-2 as a general regulator of cell chemotaxis induced by other chemotactic agents and integrins is discussed.
Mol Cell Biol 1999 Apr
PMID:Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility. 1008 79

Thrombospondin-1 (TSP) induces endothelial cell (EC) actin reorganization and focal adhesion disassembly and influences multiple EC functions. To determine whether TSP might regulate EC-EC interactions, we studied the effect of exogenous TSP on the movement of albumin across postconfluent EC monolayers. TSP increased transendothelial albumin flux in a dose-dependent manner at concentrations >/=1 microg/ml (2.2 nM). Increases in albumin flux were observed as early as 1 h after exposure to 30 microg/ml (71 nM) TSP. Inhibition of tyrosine kinases with herbimycin A or genistein protected against the TSP-induced barrier dysfunction by >80% and >50%, respectively. TSP-exposed monolayers exhibited actin reorganization and intercellular gap formation, whereas pretreatment with herbimycin A protected against this effect. Increased staining of phosphotyrosine-containing proteins was observed in plaque-like structures and at the intercellular boundaries of TSP-treated cells. In the presence of protein tyrosine phosphatase inhibition, TSP induced dose- and time-dependent increments in levels of phosphotyrosine-containing proteins; these TSP dose and time requirements were compatible with those defined for EC barrier dysfunction. Phosphoproteins that were identified include the adherens junction proteins focal adhesion kinase, paxillin, gamma-catenin, and p120(Cas). These combined data indicate that TSP can modulate endothelial barrier function, in part, through tyrosine phosphorylation of EC proteins.
Mol Biol Cell 1999 May
PMID:Thrombospondin-1 induces tyrosine phosphorylation of adherens junction proteins and regulates an endothelial paracellular pathway. 1023 61

Focal adhesion kinase (pp125FAK) has well-established functions in the attachment and growth of cells in culture and has been implicated as a marker of malignant progression in human tumors. To evaluate its role in the metastatic conversion of mouse skin tumors, pp125FAK activity and protein expression were examined in normal and transformed keratinocyte cell lines. Malignant mouse keratinocyte lines exhibited a reproducible increase in the specific activity of pp125FAK compared with that of nontransformed control cells. An increase in pp125FAK activity was not observed in papilloma-derived keratinocytes, indicating that this response correlated with malignant progression of cells and not cell transformation per se. Immune complex kinase assays and metabolic labeling with [32P]orthophosphate also revealed the specific loss of pp125FAK-associated proteins in the metastatic keratinocytes. Furthermore, immunocytochemical examination revealed an altered distribution of pp125FAK in the cells with malignant potential compared with normal and papilloma-inducing keratinocytes. The cells with malignant potential also exhibited reduced levels of paxillin and integrin beta1 as well as altered distribution of paxillin, reinforcing the notion that specific changes in the composition of focal adhesions contribute to the malignant conversion of mouse keratinocytes.
Mol Carcinog 1999 May
PMID:Alterations in focal adhesion kinase activity and associated proteins during malignant conversion of mouse keratinocytes. 1033 47


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