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)

Growth hormone (GH) has been shown to stimulate the mitogen-activated protein (MAP) kinases designated ERKs (extracellular signal regulated kinases) 1 and 2. One pathway by which ERKs 1 and 2 are activated by tyrosine kinases involves the Src homology (SH)-2 containing proteins SHC and Grb2. To gain insight into pathways coupling GH receptor (GHR) to MAP kinase activation and signaling molecules that might interact with GHR and its associated tyrosine kinase JAK2, we examined whether SHC and Grb2 proteins serve as signaling molecules for GH. Human GH was shown to promote the rapid tyrosyl phosphorylation of 66-, 52-, and 46-kDa SHC proteins in 3T3-F442A fibroblasts. GH also promoted binding of GHR and JAK2 to the SH2 domain of 46/52-kDa SHC protein fused to glutathione S-transferase (GST). Constitutively phosphorylated JAK2, from COS-7 cells transiently transfected with murine JAK2 cDNA, bound to SHC SH2-GST fusion protein, demonstrating that the SHC SH2 domain can bind tyrosyl-phosphorylated JAK2 in the absence of GHR. Regions of GHR required for GH-dependent tyrosyl phosphorylation of SHC were examined using Chinese hamster ovary cells expressing mutated rat GHR. In cells expressing GHR1-638 and GHR1-638(Y333,338F), GH stimulated phosphorylation of all 3 SHC proteins whereas GH stimulated phosphorylation of only the 66- and 52-kDa SHC proteins in cells expressing GHR1-454. GH had no effect on SHC phosphorylation in cells expressing GHR1-294 or GHR delta P, the latter lacking amino acids 297-311 containing the proline-rich motif required for JAK2 activation by GH. In contrast to SHC, Grb2 appeared not to interact directly with GHR or JAK2. However, Grb2 was shown to associate rapidly with SHC proteins in a GH-dependent manner. These findings suggest that GH stimulates: 1) the association of SHC proteins with JAK2.GHR complexes via the SHC-SH2 domain, 2) tyrosyl phosphorylation of SHC proteins, and 3) subsequent Grb2 association with SHC proteins. These events are likely to be early events in GH activation of MAP kinases and possibly of other responses to GH.
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PMID:Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2. 753 73

Although signaling by the epidermal growth factor (EGF) receptor is thought to be dependent on receptor tyrosine kinase activity, it is clear that mitogen-activated protein (MAP) kinase can be activated by receptors lacking kinase activity. Since analysis of the signaling pathways used by kinase-defective receptors could reveal otherwise masked capabilities, we examined in detail the tyrosine phosphorylations and enzymes of the MAP kinase pathway induced by kinase-defective EGF receptors. Following EGF stimulation of B82L cells expressing a kinase-defective EGF receptor mutant (K721M), we found that ERK2 and ERK1 MAP kinases, as well as MEK1 and MEK2 were all activated, and SHC became prominently tyrosine-phosphorylated. By contrast, kinase-defective receptors failed to induce detectable phosphorylations of GAP (GTPase-activating protein), p62, JAK1, or p91STAT1, all of which were robustly phosphorylated by wild-type receptors. These data demonstrate that kinase-defective receptors induce several protein tyrosine phosphorylations, but that these represent only a subset of those seen with wild-type receptors. This suggests that kinase-defective receptors activate a heterologous tyrosine kinase with a specificity different from the EGF receptor. We found that kinase-defective receptors induced ErbB2/c-Neu enzymatic activation and ErbB2/c-Neu binding to SHC at a level even greater than that induced by wild-type receptors. Thus, heterodimerization with and activation of endogenous ErbB2/c-Neu is a possible mechanism by which kinase-defective receptors stimulate the MAP kinase pathway.
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PMID:An incomplete program of cellular tyrosine phosphorylations induced by kinase-defective epidermal growth factor receptors. 753 32

The protein tyrosine kinase PYK2, which is highly expressed in the central nervous system, is rapidly phosphorylated on tyrosine residues in response to various stimuli that elevate the intracellular calcium concentration, as well as by protein kinase C activation. Activation of PYK2 leads to modulation of ion channel function and activation of the MAP kinase signalling pathway. PYK2 activation may provide a mechanism for a variety of short- and long-term calcium-dependent signalling events in the nervous system.
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PMID:Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. 765 31

The protein tyrosine kinases JAK1 and JAK2 are phosphorylated tyrosine after the interaction of granulocyte colony-stimulating factor (G-CSF) with its transmembrane receptor. So too is Stat3, a member of the STAT family of transcriptional activators thought to be activated by the JAK kinases. Truncated G-CSF receptor (G-CSF-R) mutants were used to determine the different regions of the cytoplasmic domain necessary for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK. We have shown that G-CSF-induced tyrosine phosphorylation and kinase activation of JAK2 requires the membrane proximal 57 amino acids of the cytoplasmic domain. In contrast, maximal Stat3 tyrosine phosphorylation required amino acids 96 to 183 of the G-CSF-R cytoplasmic domain, Stat3 DNA binding could occur with a receptor truncated 96 amino acids from the transmembrane domain and containing a single tyrosine residue, but was reduced in comparison with the full-length receptor. Together with the tyrosine phosphorylation of Stat3, this finding suggests that additional Stat3 does not appear to be required for proliferation. MAP kinase tyrosine phosphorylation correlated with both the proliferative response and JAK2 activation.
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PMID:Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK. 757 36

Several investigations have clearly indicated that plasma concentrations of insulin-like growth factor I (IGF-I) decrease with age and contribute to the decrease in tissue function that is characteristic of aging animals and man. Plasma IGF-I is regulated by GH released from the pituitary gland, and although data demonstrate a decline in GH secretion with age, GH receptor (GHR) density in liver tissue has been reported to increase. In this study, the effects of aging on GHR signal transduction were assessed in hepatic tissue to determine whether alterations in the response to GH contribute to the decline in IGF-I. Liver slices from female C57BL/6 mice (10, 17, and 31 months old) were prepared in medium and stimulated with GH. Basal GHR binding increased more than 2-fold in 31-month-old animals compared to that in either 10- or 17-month-old animals (P < 0.01), whereas the Ka values were similar in the three age groups. However, GH (2 nM)-induced IGF-I gene expression decreased dramatically with age (P < 0.01). In 10-month-old animals, GH-induced phosphorylation of the GHR complex was maximal 10 min after the addition of hormone, whereas GH-induced MAP kinase activity was maximal at 15 min. GH-induced JAK2 kinase and GHR complex phosphorylation as well as MAP kinase activity were significantly lower in 31-month-old animals than in either the 10- or 17-month-old groups (P < 0.05). The results of this study demonstrate that GH induces phosphorylation of JAK2 and the GHR complex, activates MAP kinase, and increases the expression of IGF-I messenger RNA in liver. In 17-month-old animals, decreases in IGF-I gene expression were evident that were not directly associated with diminished GHR complex phosphorylation or MAP kinase activity. By 31 months, there was a decrease in IGF-I gene expression that was associated with a marked decline in JAK2 and GHR complex phosphorylation. These data suggest that the signal transduction pathway for GH is impaired with age and that these changes may contribute to the decline in IGF-I gene expression.
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PMID:Decreases in growth hormone receptor signal transduction contribute to the decline in insulin-like growth factor I gene expression with age. 766 76

The growth hormone receptor (GHR) belongs to the family of the prolactin and cytokine receptors. The full length receptor in a 620 amino acid protein with a unique transmembrane domain. The GH binding protein (GHBP) corresponds to the extracellular domain of the membrane GHR. In all human tissues tested, one form of 4.5 kb for the GHR mRNA was detected, suggesting that GHBP is generated through proteolytic cleavage of the membrane receptor. The three dimensional crystollographic structure of GHBP-hGH complex has identified a homodimer made of two receptor molecules and one molecule of hGH. Hormone-induced receptor dimerisation appears to be crucial for signal transduction. Functional tests using the GH effect on transcription of genes, such as SP12.1 and beta lactoglobulin, have been developed to define the sequences of the receptor which are important for signaling. A proline-rich juxtamembranous sequence, called Box 1, is important for GH effects on gene transcription, on MAP kinase activity, on cell proliferation, and on JAK2 activation. JAK2 has been identified to be a GHR-associated tyrosine kinase. The first 46 amino acids of the cytoplasmic domain are necessary for JAK2 and MAP kinase activation whereas a C-Ter sequence is necessary for the transcriptional effect. Substrates for JAK2, other than the receptor itself, have to be identified. Good candidates are the transcription factors STAT.
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PMID:[Growth hormone receptor. Structure and signal transduction]. 767 6

In the endothelial cell line EAhy 926, 1-oleoyl-lysophosphatidic acid (LPA) stimulated the tyrosine phosphorylation of the pp42 isoform of mitogen-activated protein (MAP) kinase. Maximum phosphorylation was observed within 5 min of LPA addition, but the response was sustained for up to 120 min. Re-addition of LPA after 60 min stimulated a further sustained increase in the tyrosine phosphorylation of MAP kinase. In cells pretreated with phorbol 12-myristate 13-acetate (PMA; 24 h) or preincubated with the protein kinase C inhibitor Ro-318220, LPA-induced tyrosine phosphorylation of pp42 MAP kinase was substantially reduced at 2 min but potentiated at 60 min. Ro-318220 in combination with either PMA or pertussis toxin pretreatment abolished the LPA response at all time points, suggesting an involvement of protein kinase C in the pertussis toxin-sensitive part of the pathway. Agents which raised intracellular cyclic AMP levels did not affect the initial phase of LPA-stimulated MAP kinase activation, but abolished the late phase. However, this effect was prevented by Ro-318220, implicating a greater role for protein kinase C than protein kinase A in the regulation of sustained MAP kinase responses. LPA stimulated an increase in the tyrosine phosphorylation of focal adhesion kinase pp125 (pp125FAK) in EAhy 926 cells which was both protein kinase C- and pertussis toxin-independent. These results are discussed in terms of the pathways regulating both MAP kinase and pp125FAK in response to LPA in the EAhy 926 endothelial cells line.
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PMID:Regulation of lysophosphatidic acid-stimulated tyrosine phosphorylation of mitogen-activated protein kinase by protein kinase C- and pertussis toxin-dependent pathways in the endothelial cell line EAhy 926. 774 5

The human cholecystokinin (CCK)B/gastrin receptor was stably transfected into Rat1 fibroblasts to examine the signaling pathways mediated by this seven-transmembrane, G protein-linked receptor. We report here that binding of CCK-8 or gastrin to the CCKB/gastrin receptor induced phosphoinositide breakdown and led to a rapid, transient, and concentration-dependent increase in intracellular Ca2+, which was completely blocked by a specific CCKB receptor antagonist. The peptides also stimulated tyrosine phosphorylation of focal adhesion kinase (p125FAK) and paxillin. Both CCK-8 and gastrin induced a dose- and time-dependent activation of MAP kinase and p74raf-1 kinase in the transfected Rat1 cells. These effects could be dissociated from protein kinase C activation and were not dependent on a functional Gi protein. Finally, both CCK-8 and gastrin induced DNA synthesis in Rat1 cells transfected with the human CCKB/gastrin receptor through a pertussis toxin-insensitive pathway. These results indicate that the neuropeptides gastrin and CCK can activate multiple signal transduction pathways and act as sole mitogens by binding to the CCKB/gastrin receptor transfected into Rat1 fibroblasts.
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PMID:The human CCKB/gastrin receptor transfected into rat1 fibroblasts mediates activation of MAP kinase, p74raf-1 kinase, and mitogenesis. 779 6

The Philadelphia translocation commonly observed in chronic myeloid leukaemia (CML) and a proportion of cases of acute leukaemia results in the creation of a chimeric fusion protein, BCR-ABL. The fusion protein exhibits an elevated tyrosine kinase activity as compared to normal ABL. Using a temperature sensitive mutant of p210 BCR-ABL (ts-p210) we find that the primary effect of BCR-ABL expression in an IL-3 dependent cell line is to prolong survival following growth factor withdrawal; only a small proportion of cells remain viable and rapidly evolve to complete growth factor independence. During passage in the presence of IL-3 at the temperature permissive for kinase activity, ts-p210 expressing cultures become dominated by completely growth factor independent cells within 10-30 days. There is also a significant difference between BCR-ABL and IL-3 mediated signalling with respect to the MAP kinase pathway; in contrast to IL-3 stimulation or v-ABL expression, BCR-ABL does not signal ERK 2 (MAP 2 kinase) activation, underlining the apparent inability of BCR-ABL to deliver an immediate proliferative signal in Ba/F3 cells. Our data suggest that growth factor independence does not simply reflect the convergence of BCR-ABL and IL-3 mediated signalling pathways and its development, at least in Ba/F3 cells, requires prolonged exposure to BCR-ABL kinase activity. We suggest that the myeloid expansion characteristic of CML may result from the prolongation of survival of myeloid progenitor cells under conditions of limiting growth factor rather than their uncontrolled proliferation.
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PMID:A temperature sensitive p210 BCR-ABL mutant defines the primary consequences of BCR-ABL tyrosine kinase expression in growth factor dependent cells. 781 29

The primary structure of the growth hormone (GH) receptor in rabbits and humans determined by complementary DNA cloning revealed a single membrane-spanning protein of approximately 620 amino acids. A binding protein (bp) specific for GH has been identified in the serum of a number of species. In rabbits and man, a single 4.5-kb transcript has been identified that encodes the full-length receptor. In rats and mice, however, a smaller transcript produced by alternative splicing has been reported which is specific for the GHbp. Recently, the X-ray crystallographic structure of GH and its receptor have clearly shown the formation of an unusual homodimer, consisting of one molecule of GH and two molecules of hGHbp. Formation of the GH dimer is a necessary prerequisite for biological activity. The transcriptional activity of wild-type and mutant forms of GH receptor has been determined by co-transfecting the promoter of a GH-responsive gene, coupled to CAT along with the receptor cDNA. A 25-amino acid region near the transmembrane domain has been shown to be important for functional activity, although 8 amino acids (known as Box 1), rich in prolines, is essential. Alanine scanning mutagenesis has revealed that individual substitution of each residue is without effect, while the replacement of the last 2 or all 4 of the prolines abolishes activity. Finally, GH has been shown to induce rapid tyrosine phosphorylation of several proteins in cells expressing the receptor, one of which has recently been identified as the kinase JAK2 and another as MAP kinase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The GH receptor and signal transduction. 786 67


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