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)

The interaction of prolactin with its receptor in the Nb2 cell line has been shown to induce the phosphorylation of cell-associated proteins and mitogenesis. It has been reported previously that one of these proteins, phosphorylated upon prolactin stimulation, was a tyrosine kinase. We have identified this kinase as JAK2, and demonstrate its association with the prolactin receptor. In addition, we show that the prolactin receptor itself becomes tyrosine phosphorylated upon ligand stimulation in Nb2 cells. These actions are time-dependent and occur rapidly after prolactin stimulation, with first the kinase being activated within 5 min and then the receptor being phosphorylated maximally at 20 min. Moreover, phosphorylation of both JAK2 and the receptor as well as Nb2 cell proliferation are dependent on the concentration of lactogenic hormone, resulting in a bell-shaped response curve similar to that observed in the two site model of hGH action. This indicates that early events in signal transduction as well as later events like mitogenesis and proliferation involve prolactin receptor dimerization. Together these data indicate that the prolactin receptor in Nb2 cells is associated to JAK2 and that upon ligand stimulation, and receptor dimerization, the kinase and the receptor are tyrosine-phosphorylated, which represents the first event in the process of prolactin receptor signal transduction in Nb2 cells.
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PMID:Prolactin-induced proliferation of Nb2 cells involves tyrosine phosphorylation of the prolactin receptor and its associated tyrosine kinase JAK2. 818 82

The present study of prolactin (PRL) receptor-mediated recruitment of signal transducers and activators of transcription (STATs) demonstrates that PRL activates STAT3, in addition to STAT1 and STAT5 as previously reported, and that STAT1, STAT3 and STAT5 are mediators of PRL effects in cells whether of lymphoid, myeloid or mammary epithelial origin. Furthermore, receptor mutants M240 and T280 that do not mediate PRL-induced JAK2 activation and cell proliferation, are also unable to mediate STAT activation, supporting the proposed model of JAK2 as the initial effector protein used by PRL receptors. On the other hand, tyrosine phosphorylation analysis and electrophoretic mobility shift assays showed that receptor mutant G328, which lacks four of the five conserved cytoplasmic tyrosine residues of PRL receptors, retained the ability to activate JAK2 and STAT1, STAT3 and STAT5. These results support the notion that phosphotyrosyl residues other than those of the receptor, i.e., JAK2, are involved in recruiting STAT proteins to the activated PRL receptor complex.
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PMID:Prolactin recruits STAT1, STAT3 and STAT5 independent of conserved receptor tyrosines TYR402, TYR479, TYR515 and TYR580. 873 72

The peptide hormone prolactin (Prl) regulates proliferation of normal and malignant mammary cells. In the present study we demonstrate that two Prl responsive cell lines, NOG-8 and T47D, activate the JAK2-SHC-MAPK pathway in a rapid and transient manner. Within 1 min of Prl treatment there was an increase in association of JAK2 with SHC, followed by rapid phosphorylation of both the 52 kDa and 46 kDa SHC proteins. Grb2 and Sos associated with the SHC proteins within 1-3 min of Prl treatment in these mammary cells. Within 5 min of hormone treatment we observe an increase in ras-GTP suggesting activation of ras. We also showed a rapid and transient tyrosine phosphorylation of STAT5 in proliferating T47D cells which reached its peak after 30 min of Prl treatment. These results indicate that Prl receptors, after binding the ligand, activate several pathways for signal transduction leading to mitogenesis.
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PMID:Involvement of SHC, GRB2, SOS and RAS in prolactin signal transduction in mammary epithelial cells. 880 87

The growth hormone (GH) receptor belongs to the superfamily of transmembrane proteins that includes the prolactin (PRL) receptor and a number of cytokine receptors. Two forms exist for the GH receptor: the membrane-bound form is a protein of 620 amino acid residues with a unique transmembrane domain; the GH-binding protein (GHBP), which is a soluble short form, is identical to the extracellular domain of the membrane receptor. In man and many other species, GHBP is believed to result from proteolytic cleavage of the membrane receptor; in human tissues, only one mRNA form of 4.5 kb encoding the full-length receptor has been detected. In rodents, GHBP is encoded by a specific mRNA of 1.2kb. Binding of GH to its receptor results in dimerization of the receptor, phosphorylation of the tyrosine kinase JAK2 and of the receptor, followed by a cascade of protein phosphorylations. Transcription factors belonging to the signal transducers and activators of transcription (STAT) family are involved in the effects of GH on the transcription of genes such as c-fos, serine protease inhibitor Spi 2.1 and beta-casein. GH is able to activate several STAT proteins including STAT1, 3 and 5. The JAK-STAT pathway is a main pathway for GH effects on gene transcription. Other signalling molecules are involved in GH action through different pathways: GH is able to activate mitogen activated protein (MAP) kinases; the hormone can utilize insulin receptor substrate-1 (IRS-1) and induces the association of phosphatidylinositol 3-kinase with IRS-1. Two main functional regions have been defined in the cytoplasmic domain of the GH receptor by testing the activity of mutant forms of the receptor in several systems: Box 1, a proline-rich sequence in the membrane proximal part, is necessary for all GH effects and is probably the region of association with JAK2; the C-terminal region is required for the induction of specific genes. Other molecules involved in the mechanisms of action of GH remain to be identified. As the same signalling pathways are used by many ligands, explanations for the specificity of the cellular effects have to be determined.
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PMID:Growth hormone receptor signalling. 885 42

Dopaminergic system seems to influence the regulation of insulin secretion, although in man conflicting data are reported. Furthermore, bromocriptine (BRC), a dopaminergic agonist, has been recently found to inhibit the seasonally occurring hyperinsulinemia and the increase in body weight in the hamster. On this basis, we investigated the effect of BRC on spontaneous and stimulated insulin secretion in human obesity. Six obese (BMI: 33.2 +/- 1.6 Kg/m2) underwent the administration of: 1) arginine (ARG, 0.5 g/Kg iv in 30 min), 2) BRC (2.5 mg po), 3) ARG+BRC. In each test plasma glucose and serum insulin, growth hormone (GH) and prolactin levels were determined. BRC did not significantly reduce spontaneous and ARG-induced insulin release. Baseline and stimulated glucose levels were also unchanged. BRC determined an increase in GH levels (3.7 +/- 1.3 vs 0.5 +/- 0.3 microgram/l, p < 0.05), but failed to modify the somatotrope responsiveness to ARG. On the other hand, both spontaneous and stimulated PRL secretion were reduced by BRC (2.5 +/- 0.4 vs 6.7 +/- 1.1 micrograms/l, p < 0.05 and 0.8 +/- 1.9 vs 11.0 +/- 2.1 micrograms/l, p < 0.05, respectively). Our results show that in obese patients the acute activation of dopaminergic receptors by bromocriptine fails to modify both basal and ARG-induced insulin release, while inhibits spontaneous and stimulated PRL secretion. Our data also show that the low GH response to arginine in obesity is not improved by the coadministration of bromocriptine, in agreement with the hypothesis that both substances act by the same mechanism, i.e. inhibition of endogenous somatostatin release.
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PMID:Effect of bromocriptine on insulin, growth hormone and prolactin responses to arginine in obesity. 886 1

Growth hormone (GH) and prolactin (PRL) exert long-term effects on cellular metabolism, growth, and development through changes in gene expression and protein biosynthesis that are initiated by hormone binding to specific cell-surface receptors. Recent studies have demonstrated that ligand-induced activation of both GH and PRL receptors leads to the tyrosine phosphorylation of multiple intracellular proteins by the identical non-receptor tyrosine kinase, JAK2. We have shown previously that in vivo administration of human recombinant GH rapidly stimulated the inducible transcription factors, Stats1, 3, and 5, and acutely altered gene transcription in the liver. Because human GH can bind to both lactogenic and somatogenic receptors with high affinity, in this study we have addressed the question of specificity of the hormonal response by examining the early nuclear events following a single injection of rat GH or rat PRL to hormone-deficient hypophysectomized female rats. We find that PRL stimulated tyrosine phosphorylation of Stat5, induced nuclear protein binding to the GH-responsive element of the serine protease inhibitor (Spi) 2.1 promoter, and activated Spi 2.1 gene expression. These acute actions of rat PRL were modest compared to the effects of rat GH. GH treatment induced tyrosine phosphorylation of several hepatic nuclear proteins, activated Stats1, 3, and 5, stimulated Spi 2.1 gene expression, and inhibited albumin gene transcription. All of the effects of rat GH paralleled responses to human GH that we have measured previously. Based on these results, it is likely that most of the actions of human GH in the liver are mediated by the GH receptor rather than by the PRL receptor. The diminished response to PRL may be secondary to the high density of short PRL receptor isoforms in the liver, which do not participate effectively in ligand-induced signal transmission.
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PMID:Contrasting acute in vivo nuclear actions of growth hormone and prolactin. 889 12

The signal transduction mechanism involved in human placental lactogen (hPL) was studied. We have identified that hPL rapidly stimulated the tyrosine phosphorylation of at least 7 proteins including Janus Kinases (JAK1 and JAK2) and a signal transducer and activator of transcription protein (Stat3). This is the first evidence that the JAK-STAT pathway is involved in the hPL signaling. Moreover, two unknown proteins which were different from STAT proteins (Stat1, 3 and 5) in sizes were predominantly tyrosine-phosphorylated. Because human growth hormone (hGH) activates Stat1, 3, 5 and human prolactin (hPRL) activates Stat5, these results show that hPL uses a unique signal transduction pathway which is different from hGH and hPRL.
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PMID:Participation of JAK, STAT and unknown proteins in human placental lactogen-induced signaling: a unique signaling pathway different from prolactin and growth hormone. 913 82

Treatment of T47-D human breast carcinoma cells with recombinant prolactin (rhPRL) induced a concentration- and time-dependent increase in the phosphotyrosine content of JAK2. rhPRL also stimulated JAK2 tyrosine phosphorylation more weakly in three other breast carcinoma lines, MCF-7, ZR-75-1 and MDA-MB-231. Furthermore it stimulated tyrosine phosphorylation of two isoforms of the transcriptional activator STAT5, STAT5a and STAT5b. Surprisingly, rhPRL treatment of T47-D cells also stimulated tyrosine phosphorylation of focal adhesion kinase (FAK), as determined by immunoprecipitation with anti-phosphotyrosine antibody followed by immunoblotting with a specific FAK antibody. The effect of rhPRL was rapid and concentration-dependent, being maximal at 5 ng/ml. At rhPRL concentrations above 25 ng/ml, FAK tyrosine phosphorylation declined but remained above control levels at 100 ng/ml. rhPRL also stimulated paxillin tyrosine phosphorylation in T47-D cells with similar concentration- and time-dependence. In a second human breast carcinoma cell line, MCF-7, rhPRL produced very similar effects on FAK and paxillin tyrosine phosphorylation. These findings identify a new protein tyrosine kinase pathway in the action of the lactogenic hormone rhPRL and represent the first report that a hormone acting through a member of the haemopoietin receptor superfamily can regulate the FAK/paxillin pathway.
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PMID:Prolactin stimulates the JAK2 and focal adhesion kinase pathways in human breast carcinoma T47-D cells. 916 61

The interaction of prolactin (PRL) with its receptor leads to activation of the tyrosine kinase, Janus kinase 2 (JAK2). In the cytoplasmic juxtamembrane region, a short segment (Box 1) which is conserved in other receptors of the PRL/growth hormone (GH)/cytokine receptor family, is required for signal transduction. To assess the contribution of the different amino acids of Box 1, individual alanine substitutions of all residues, grouped substitution of four prolines (4PA mutant) and individual leucine replacement of the two last prolines (P248L and P250L mutants) were introduced. Here we show that P250L and 4PA (i) inhibit PRL-induced transactivation of a luciferase reporter governed by a beta-caseine gene promoter; (ii) decrease in JAK2 tyrosine kinase activity in biotinylated-PRL precipitates; (iii) impair the interaction between PRLR and JAK2, as evidenced by lack of co-immunoprecipitation, (iv) and prevent the activation of signal transducer and activator of transcription (Stat) as determined by absence of tyrosine phosphorylation of Stat5. Our data suggest that the Box 1 region of the PRL receptor and particularly the last proline is critical for JAK2 association and subsequent activation. These results support the notion that the tyrosine kinase JAK2 is implicated in activation of downstream protein effectors such as Stat5, which are involved in transcription of PRL-responsive genes.
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PMID:The last proline of Box 1 is essential for association with JAK2 and functional activation of the prolactin receptor. 920 3

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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