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

We have investigated mechanisms involved in integrin-mediated signal transduction in platelets by examining integrin-dependent phosphorylation and activation of a newly identified protein tyrosine kinase, pp125FAK (FAK, focal adhesion kinase). This kinase was previously shown to be localized in focal adhesions in fibroblasts, and to be phosphorylated on tyrosine in normal and Src-transformed fibroblasts. We show that thrombin and collagen activation of platelets causes an induction of tyrosine phosphorylation of pp125FAK and that pp125FAK molecules isolated from activated platelets display enhanced levels of phosphorylation in immune-complex kinase assays. pp125FAK was not phosphorylated on tyrosine after thrombin or collagen treatment of Glanzmann's thrombasthenic platelets deficient in the fibrinogen receptor GPIIb-IIIa, or of platelets pretreated with an inhibitory monoclonal antibody to GP IIb-IIIa. Fibrinogen binding to GP IIb-IIIa was not sufficient to induce pp125FAK phosphorylation because pp125FAK was not phosphorylated on tyrosine in thrombin-treated platelets that were not allowed to aggregate. These results indicate that tyrosine phosphorylation of pp125FAK is dependent on platelet aggregation mediated by fibrinogen binding to the integrin receptor GP IIb-IIIa. The induction of tyrosine phosphorylation of pp125FAK was inhibited in thrombin- and collagen-treated platelets preincubated with cytochalasin D, which prevents actin polymerization following activation. Under all of these conditions, there was a strong correlation between the induction of tyrosine phosphorylation of pp125FAK in vivo and stimulation of the phosphorylation of pp125FAK in vitro in immune-complex kinase assays. This study provides the first genetic evidence that tyrosine phosphorylation of pp125FAK is dependent on integrin-mediated events, and demonstrates that there is a strong correlation between tyrosine phosphorylation of pp125FAK in platelets, and the activation of pp125FAK-associated phosphorylating activity in vitro.
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PMID:Integrin-dependent phosphorylation and activation of the protein tyrosine kinase pp125FAK in platelets. 138 45

The protein-tyrosine kinases (PTKs) are a burgeoning family of proteins, each of which bears a conserved domain of 250 to 300 amino acids capable of phosphorylating substrate proteins on tyrosine residues. We recently exploited the existence of two highly conserved sequence elements within the catalytic domain to generate PTK-specific degenerate oligonucleotide primers (A. F. Wilks, Proc. Natl. Acad. Sci. USA 86:1603-1607, 1989). By application of the polymerase chain reaction, portions of the catalytic domains of several novel PTKs were amplified. We describe here the primary sequence of one of these new PTKs, JAK1 (from Janus kinase), a member of a new class of PTK characterized by the presence of a second phosphotransferase-related domain immediately N terminal to the PTK domain. The second phosphotransferase domain bears all the hallmarks of a protein kinase, although its structure differs significantly from that of the PTK and threonine/serine kinase family members. A second member of this family (JAK2) has been partially characterized and exhibits a similar array of kinase-related domains. JAK1 is a large, widely expressed membrane-associated phosphoprotein of approximately 130,000 Da. The PTK activity of JAK1 has been located in the C-terminal PTK-like domain. The role of the second kinaselike domain is unknown.
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PMID:Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. 184 70

A tyrosine protein kinase activity has been partially purified from calf thymus using the phosphorylation of the tyrosine-containing peptide angiotensin I as an assay. Detergent extracts of calf thymus possessed only low levels of specific peptide phosphorylating activity when assayed at low ionic strength. The inclusion of NaCl at a concentration of 2 M stimulated endogenous tyrosine protein kinase activity, while the activity of other endogenous kinases was inhibited. This sensitivity to NaCl was retained following partial purification of the enzyme. The phosphorylation of other substrates such as casein or the R-R-SRC peptide (Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly) by the tyrosine protein kinase was less sensitive to NaCl. Phosphorylation of the PK-1 peptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly) by the purified catalytic subunit of cAMP-dependent protein kinase was inhibited by NaCl. The effect of NaCl on angiotensin I phosphorylation could be mimicked by KCl or sodium acetate. The principal effect of NaCl was to increase the Vmax of the enzyme for the phosphorylation of angiotensin I. At low ionic strength, Mn2+ and Co2+ were the preferred required divalent cations. At elevated NaCl concentrations Mg2+ was preferred, with half-maximal activation occurring at 35 mM Mg2+. By conducting peptide phosphorylation assays in the presence of elevated levels of Mg2+ and NaCl, tyrosine protein kinase activity can readily be detected in extracts from cell lines that express low levels of the enzyme.
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PMID:Properties of a tyrosine protein kinase from calf thymus. Response to ionic strength and divalent cations. 387 56

The chimeric BCR/ABL protein is characteristic of Philadelphia (Ph)+ leukemia because it is the direct product of the Ph translocation and it has been shown to play a causal role in the genesis of leukemia. The BCR/ABL protein exhibits a deregulated tyrosine-kinase activity capable of phosphorylating different cellular substrates in vivo and in vitro. CRKL, an adaptor protein consisting of SH2 and SH3 domains in the absence of a catalytic domain, is one potential in vivo substrate of BCR/ABL. Previous experiments have shown that CRKL is phosphorylated on tyrosine in the chronic myelogenous leukemia (CML) cell line K562 and that CRKL is a substrate for ABL and for BCR/ABL in COS-1 cells. In the current study, we show that in peripheral blood cells a direct correlation exists between the presence of BCR/ABL and the phosphorylation status of CRKL. In Ph- peripheral blood cells, CRKL is present only in the nonphosphorylated form. In contrast, all BCR/ABL+ CML and acute lymphoblastic leukemia patient samples examined showed clear tyrosine-phosphorylation of CRKL. This result strongly suggests that CRKL is a biologically significant substrate for BCR/ABL and is likely to play a major role in the development of Ph+ leukemia.
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PMID:Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. 752 85

Interleukin (IL)-9 stimulates the proliferation of a variety of hematopoietic lineages through its interaction with a receptor of the cytokine receptor superfamily. In the studies presented here, we have begun to characterize the downstream signaling pathways activated by IL-9. In addition to the activation of JAK1 and JAK3 tyrosine kinases, IL-9, unlike most hematopoietic cytokines but similar to IL-4, induces the tyrosine phosphorylation of a 170-kDa protein that is related to the insulin receptor substrate-1 (IRS-1). We further demonstrate for the first time that IRS-1 is not only associated with JAK1 but also tyrosine phosphorylated and functionally involved in IL-9 signaling in TS1 lymphocytes transfected with the murine IRS-1 cDNA. Cotransfection studies and in vitro experiments directly demonstrate that JAK1, JAK2, or JAK3 is capable of tyrosine phosphorylating IRS-1, suggesting a functional role for these kinases in vivo. Lastly, we demonstrate that IL-9 induces the tyrosine phosphorylation of Stat3 and in this regard differs from IL-4, which triggers tyrosine phosphorylation of Stat6. Taken together, these results strongly suggest that IL-9 and IL-4 utilize common and unique signaling pathways via inducing the similar and distinct tyrosine-phosphorylated proteins.
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PMID:Interleukin-9 induces tyrosine phosphorylation of insulin receptor substrate-1 via JAK tyrosine kinases. 754 89

Fertilization results in the tyrosine phosphorylation of several egg proteins within minutes of sperm-egg binding, although the identity of the kinase(s) involved and the mechanism of regulation is not known. In the present study, we have used site-directed antibodies based on the predicted amino acid sequence of a sea urchin egg transcript that shares significant homology with members of the ABL family of protein tyrosine kinases. These antibodies identified a 220-kDa protein kinase, highly enriched in the egg cortex, where it is tightly associated with detergent-insoluble cytoskeletal elements. The enzyme is capable of phosphorylating synthetic peptide substrates which were used to characterize the kinase activity in an immune-complex assay. Measurement of the protein tyrosine kinase activity immunoprecipitated at different times after fertilization revealed that the level of kinase activity is transiently elevated during the first few minutes postinsemination. Western blot analysis indicated that the amount of the 220-kDa protein did not increase significantly during this period, so the increased kinase activity probably results from activation of the enzyme. These in vitro studies indicate that the 220-kDa abl-related kinase is one of the protein kinases activated during fertilization and suggest that it may play a role in the egg activation process.
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PMID:Identification of an abl-related protein tyrosine kinase in the cortex of the sea urchin egg: possible role at fertilization. 804 47

Mouse c-Abl type IV and human BCR/ABL proteins have been expressed in insect cells using the baculovirus system. The proteins were expressed as full-length polypeptides as judged by electrophoresis in denaturing gels. They were identified by immunoprecipitation and immunoblotting with antibodies against ABL peptides and, for BCR/ABL, against a BCR peptide. In these immunoprecipitates both proteins gave autophosphorylation principally on tyrosine. Both proteins were active tyrosine kinases, phosphorylating a variety of tyrosine-containing substrates. In fresh extracts both proteins contained phosphotyrosine as shown by Western blots with antiphosphotyrosine antibodies. Partial purification could be achieved readily using ion exchange columns, and the BCR/ABL protein, p210BCR/ABL, could be further purified to near-homogeneity using an antiphosphotyrosine column. Both enzymes required a divalent metal ion for activity. At low concentrations of ATP (2 microM) and with angiotensin II as substrate both enzymes were activated by Mn2+ or by Mg2+. No major differences in catalytic properties were found between the two isolated enzymes in solution. The oncogenic properties of p210BCR/ABL may be due to its different subcellular location, or to the presence of an intracellular inhibitor of c-Abl that does not inhibit BCR/ABL, or to altered substrate-specificity such that it can phosphorylate a unique substrate which is not recognised by c-Abl.
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PMID:Comparison of baculovirus-expressed c-Abl and BCR/ABL protein tyrosine kinases. 848

Convulxin, a powerful platelet activator, was isolated from Crotalus durissus terrificus venom, and 20 amino acid N-terminal sequences of both subunits were determined. These indicated that convulxin belongs to the heterodimeric C-type lectin family. Neither antibodies against GPIb nor echicetin had any effect on convulxin-induced platelet aggregation showing that, in contrast to other venom C-type lectins acting on platelets, GPIb is not involved in convulxin-induced platelet activation. In addition, partially reduced/denatured convulxin only affects collagen-induced platelet aggregation. The mechanism of convulxin-induced platelet activation was examined by platelet aggregation, detection of time-dependent tyrosine phosphorylation of platelet proteins, and binding studies with 125I-convulxin. Convulxin induces signal transduction in part like collagen, involving the time-dependent tyrosine phosphorylation of Fc receptor gamma chain, phospholipase Cgamma2, p72(SYK), c-Cbl, and p36-38. However, unlike collagen, pp125(FAK) and some other bands are not tyrosine-phosphorylated. Convulxin binds to a glycosylated 62-kDa membrane component in platelet lysate and to p62/GPVI immunoprecipitated by human anti-p62/GPVI antibodies. Convulxin subunits inhibit both aggregation and tyrosine phosphorylation in response to collagen. Piceatannol, a tyrosine kinase inhibitor with some specificity for p72(SYK), showed differential effects on collagen and convulxin-stimulated signaling. These results suggest that convulxin uses the p62/GPVI but not the alpha2beta1 part of the collagen signaling pathways to activate platelets. Occupation and clustering of p62/GPVI may activate Src family kinases phosphorylating Fc receptor gamma chain and, by a mechanism previously described in T- and B-cells, activate p72(SYK) that is critical for downstream activation of platelets.
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PMID:Platelet activation and signal transduction by convulxin, a C-type lectin from Crotalus durissus terrificus (tropical rattlesnake) venom via the p62/GPVI collagen receptor. 915 5

X-linked agammaglobulinemia patients and X-linked immunodeficient (xid) mice possess mutations in the Bruton's tyrosine kinase (Btk kinase) gene and display defects in B cell development and activation by sIg cross-linking. Btk is an early activation kinase in sIg-cross-linked B cells. xid does not ablate Btk protein kinase activity, and immediate signal transduction events, such as tyrosine phosphorylation, occur in sIg-activated xid B cells. These cells do not subsequently progress into cell division and have a high rate of apoptosis, which has been shown to correlate with an absence of sIg-mediated induction of the bcl-xL protein. To establish the point where Btk activity is critical for progression beyond immediate signaling, we examined early and late events in sIg-cross-linked xid B cells. Induction of proto-oncogenes and nuclear factors occurred normally in xid cells. However, induction of cyclins and increased GAPDH mRNA was not observed in xid cells. Degradation of the cyclin inhibitor p27Kip1 occurred normally in xid cells. After 24 h of culture with anti-mu, the remaining live, nonapoptotic xid cells were enlarged, viable, and primed for subsequent stimulation by LPS. Our data suggest that the Btk kinase is not essential for several G1 events and that the failure of sIg-activated xid B cells to enter cell cycle correlates with a defect of cyclin induction. Moreover, these data suggest that Btk is important not only for immediate events following B cell activation and control of apoptosis but also for subsequent events leading to cyclin activation.
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PMID:xid affects events leading to B cell cycle entry. 920 Apr 48

We previously reported that a single intraperitoneal injection of prolactin (PRL) in female adult rats rapidly and transiently activates mitogen-activated protein kinase (MAPK) in the liver (Piccoletti et al., (1994) Biochem. J. 303, 429-423). Here we analysed the PRL signalling pathway that accounts for MAPK activation. We found that total liver MAPK kinase-1 phosphorylating activity and Raf-1 activity significantly increase after PRL treatment, following a time course that accounts for the activation of MAPK. We also identified a significant increase in the phosphotyrosine content of the 52 kDa Shc protein, accompanied by an increase in Shc coimmunoprecipitated Grb2, which suggests the Ras involvement by PRL. We found that Janus kinase (JAK)2 tyrosine kinase, which appears constitutively associated with the PRL receptor expressed in the liver, is activated and associated with Shc proteins after in vivo PRL treatment. Taken together our data provide evidence that in vivo PRL activates the Shc Ras Raf MAPK cascade in the liver by the involvement of JAK2 and suggests the possibility that the liver short form of PRL receptor plays a role in triggering this signalling pathway.
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PMID:Signal transduction pathway of prolactin in rat liver. 948 13


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