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)

Bruton's tyrosine kinase (Btk), a cytoplasmic protein-tyrosine kinase, plays a pivotal role in B cell activation and development. Mutations in the pleckstrin homology (PH) domain of the Btk gene cause human X-linked agammaglobulinemia (XLA) and murine X-linked immunodeficiency (Xid). In this paper, we report that the PH domain of Btk functions as an inositol 1,3,4,5-tetrakisphosphate (IP4), inositol 1,3,4,5,6-pentakisphosphate, and inositol 1,2,3,4,5,6-hexakisphosphate (IP6) binding domain (Kd of approximately 40 nM for IP4), and that all of the XLA (Phe replaced by Ser at position 25 (F25S), R28H, T33P, V64F, and V113D) and Xid mutations (R28C) found in the PH domain result in a dramatic reduction of IP4 binding activity. Furthermore, the rare alternative splicing variant, with 33 amino acids deleted in the PH domain, corresponding to exon 3 of the Btk gene, also impaired IP4 binding capacity. In contrast, a gain-of-function mutant called Btk*, which carries a E41K mutation in the PH domain, binds IP6 with two times higher affinity than the wild type. Our data suggest that B cell differentiation is closely correlated with the IP4 binding capacity of the PH domain of Btk.
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PMID:Mutation of the pleckstrin homology domain of Bruton's tyrosine kinase in immunodeficiency impaired inositol 1,3,4,5-tetrakisphosphate binding capacity. 893 85

The human BCR gene encodes a protein with serine/threonine kinase activity and regulatory domains for the small G-proteins RAC and CDC42. Previous work in our laboratory has established that BCR is a substrate for c-FES, a non-receptor tyrosine kinase linked to myeloid growth and differentiation. Tyrosine phosphorylation led to the association of BCR with the RAS guanine nucleotide exchange complex GRB2-SOS in vivo via the GRB2 SH2 domain, linking BCR to RAS signaling (Maru, Y., Peters, K. L., Afar, D. E. H., Shibuya, M., Witte, O. N., and Smithgall, T. E. (1995) Mol. Cell. Biol. 15, 835-842). In the present study, we demonstrate that BCR Tyr-246 and at least one of the closely spaced tyrosine residues, Tyr-279, Tyr-283, and Tyr-289 (3Y cluster), are phosphorylated by FES both in vitro and in 32Pi-labeled cells. Mutagenesis of BCR Tyr-177 to Phe completely abolished FES-induced BCR binding to the GRB2 SH2 domain, identifying Tyr-177 as an additional phosphorylation site for FES. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1. These data show that tyrosine phosphorylation by FES affects the interaction of BCR with multiple signaling partners and suggest a general role for BCR in non-receptor protein-tyrosine kinase regulation and signal transduction.
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PMID:Co-expression with BCR induces activation of the FES tyrosine kinase and phosphorylation of specific N-terminal BCR tyrosine residues. 895 35

The receptors for human interleukin-3 (IL-3) and human granulocyte-macrophage colony-stimulating factor (GM-CSF), hIL-3R, hGM-CSFR, respectively, consists of two subunits, alpha and beta, both of which are members of the cytokine receptor superfamily. Phosphorylation of tyrosine residues in the hGMR beta subunit and several cellular proteins is observed after hGM-CSF stimulation. We analyzed the role of tyrosine residues in the hGMR beta subunit and the nature of tyrosine kinase, JAK2, in hGMR signal transduction using several hGMR beta subunit mutants. In addition to the box1 region, a membrane distal region (a.a. 544-589) of the hGMR beta was required for c-fos activation. Only one tyrosine residue (Tyr577) existed within the region 544 to 589, and substitution of Tyr577 to phenylalanine in GMR beta 589 resulted in loss of c-fos activation. In contrast, the same substitution in a wild type receptor did not affect GM-CSF induced activities such as c-fos messenger RNA (mRNA) induction and proliferation, but the substitution abolished Shc phosphorylation. These results suggest that the activation of Shc is not essential for c-fos activation and several tyrosine residues cooperate for c-fos activation. It is well documented that IL-3 or GM-CSF activate JAK2 in BA/F3 cells. The role of JAK2 in IL-3/GM-CSF functions, however, is largely unknown. We examined the role of JAK2 in GM-CSF induced signaling pathways. Dominant negative JAK2 (delta JAK2) lacking the C-terminus kinase domain suppressed IL-3/GM-CSF induced c-fos activation and c-myc activation and proliferation, suggesting that JAK2 was involved in both signaling pathways. Protein tyrosine phosphatase SHP-2 (also called PTP 1D) and Shc were phosphorylated by IL-3/GM-CSF in BA/F3 cells; however, these phosphorylation events were inhibited by the expression of delta JAK2. Taken together, these results indicate the JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.
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PMID:Roles of JAK kinases in human GM-CSF receptor signal transduction. 897 26

The CD28 cell surface receptor provides an important costimulatory signal for T cells necessary for their response to Ag. Early events in CD28 signaling include recruitment and activation of phosphatidylinositol 3-kinase (PI3-kinase) and activation of the protein tyrosine kinases (PTKs), LCK and EMT. Recruitment and activation of PI3-kinase is known to be dependent upon phosphorylation of tyrosine 173 of the CD28 cytoplasmic tail contained within a YMNM motif. By contrast, little is known of which residues of the CD28 tail, including tyrosines, are required for the activation of PTKs. To address this we studied the ability of truncation mutants and tyrosine to phenylalanine substitution mutants of the CD28 cytoplasmic tail to activate LCK and EMT in Jurkat T leukemia cells. Our results indicate that 1) activation of EMT is partially dependent upon tyrosine 173 of the CD28 tail, although it does not require PI3-kinase activation; 2) activation of LCK is independent of CD28 cytoplasmic tail tyrosine residues; and 3) elements sufficient for the activation of both kinases are contained within the first half of the tail. In addition we studied the CD28 tail as a substrate for both PTKs in in vitro kinase assays. We demonstrate that EMT can phosphorylate all four tyrosines of the CD28 tail, in contrast to LCK, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor.
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PMID:Analysis of CD28 cytoplasmic tail tyrosine residues as regulators and substrates for the protein tyrosine kinases, EMT and LCK. 899 71

Interaction between erythropoietin (EPO) and its membrane receptor induces the proliferation and differentiation of erythroid progenitors. EPO has been shown to activate the JAK2-STAT5 pathway in various hematopoietic cell lines, although the physiological role of this pathway is unclear. We have previously shown that epidermal growth factor activates a chimeric receptor bearing the extracellular domain of the epidermal growth factor receptor linked to the cytoplasmic domain of the EPO receptor, resulting in proliferation of interleukin-3-dependent hematopoietic cells and erythroid differentiation (globin synthesis) of EPO-responsive erythroleukemia cells. In the present study, we introduced various deletion and tyrosine to phenylalanine substitution in the cytoplasmic domain of the chimeric receptor and expressed these mutant chimeras in an EPO-responsive erythroleukemia cell line, ELM-I-1. Mutant chimeric receptors retaining either Tyr343 or Tyr401 could activate STAT5, judged by tyrosine-phosphorylation of STAT5 and induction of CIS, a target gene of STAT5. These mutants were able to induce erythroid differentiation. However, a chimeric receptor containing both Y343F and Y401F mutations could not activate STAT5 nor induce erythroid differentiation. Thus, Tyr343 or Tyr401 of the EPO receptor are independently necessary for erythroid differentiation as well as STAT5 activation. Moreover, exogenous expression of dominant-negative STAT5 suppressed EPO-dependent erythroid differentiation. These findings suggest that STAT5 plays an important role in erythroid differentiation through the EPO receptor cytoplasmic domain.
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PMID:STAT5 activation correlates with erythropoietin receptor-mediated erythroid differentiation of an erythroleukemia cell line. 907 29

To determine whether GH receptor (GHR) cytoplasmic tyrosine residue(s) and tyrosine phosphorylation are required for signal transduction, we have substituted the eight porcine (p) GHR cytoplasmic tyrosines with phenylalanine individually or in a stepwise manner from the C terminus. Conversely, the eight tyrosines were individually regenerated in a non-tyrosine-containing pGHR analog. Mutated pGHR cDNAs were transfected into mouse L cells (MLCs) and cell lines were established. Each individual tyrosine-substituted pGHR analogs was able to activate STAT5 (signal transducer and activator of transcription 5; previously termed pp95) at levels comparable to those of wild type pGHR. Analyses of these pGHR analogs revealed that a single tyrosine residue at position 487, 534, 566, or 627 is sufficient for STAT5 phosphorylation. This result suggested that a redundancy in tyrosine residue requirement may be employed in GH-mediated signal transduction. Also, we found that the requirement of tyrosine residues for STAT5 phosphorylation directly correlated with their phosphorylation status. Combining both STAT5 and GHR tyrosine phosphorylation results, we have deduced that Y332, Y487, Y534, Y566, and Y627 are pGHR tyrosine phosphorylation sites. Additionally, Janus kinase 2 was activated by GH in all pGHR tyrosine-substituted analogs, including one containing no intracellular tyrosines, which agrees with a previous report that Janus kinase 2 activation is independent of GHR tyrosine phosphorylation.
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PMID:Identification of growth hormone receptor (GHR) tyrosine residues required for GHR phosphorylation and JAK2 and STAT5 activation. 912 92

R- cells, a line of mouse embryo fibroblasts with a targeted disruption of the insulin-like growth factor I (IGF-I) receptor genes, are refractory to transformation by several viral and cellular oncogenes. Using colony formation in soft agar as a measure of full transformation, we report here that R- cells can be transformed by v-src, although they still cannot be transformed by the activated c-src527 (mutation at tyrosine 527 to phenylalanine), which readily transforms mouse embryo cells with a wild-type number of IGF-I receptors (W cells). Although v-src is a more potent inducer of tyrosine phosphorylation than c-src527, the extent of phosphorylation of either insulin receptor substrate 1 or Shc, two of the major substrates of the IGF-I receptor, does not seem sufficiently different to explain the qualitative difference in soft agar growth. v-src, however, is considerably more efficient than c-src527 in its ability to tyrosyl phosphorylate, in R- cells, the focal adhesion kinase, Stat1, and p130cas. These results indicate that v-src, but not c-src527, can bypass the requirement for a functional IGF-I receptor in the full transformation of mouse embryo fibroblasts and suggest that qualitative and quantitative differences between the two oncogenes can be used to identify some of the signals relevant to the mechanism(s) of transformation.
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PMID:Insulin-like growth factor I receptor signaling in transformation by src oncogenes. 919 8

The IL-3 and GM-CSF (hGMR) receptors consist of two subunits, alpha and beta, both of which are members of the cytokine receptor superfamily. Phosphorylation of tyrosine residues of hGMR beta subunit and several cellular proteins are observed with hGM-CSF stimulation. We analyzed role of tyrosine residue of hGMR beta subunit and nature of tyrosine kinase, JAK2 in hGMR signals using several hGMR beta subunit mutants. In addition to box1 region, a membrane distal region (a.a. 544-589) of hGMR beta is required for c-fos activation. Only one tyrosine residue (Tyr577) exists within the region 544-589, and substitution of Tyr577 to phenylalanine in GMR beta 589 resulted in the loss of c-fos activation. In contrast, the same substitution in a wild type receptor did not affect GM-CSF-induced activities such as c-fos mRNA induction and proliferation but abolished Shc phosphorylation. These results suggest that the activation of Shc is not essential for c-fos activation and several tyrosine residues co-ordinate to activate c-fos activation. It is well documented that IL-3 or GM-CSF activates JAK2 in BA/F3 cells. However the role of JAK2 in IL-3/GM-CSF functions is largely unknown. We examined the role of JAK2 in GM-CSF-induced signaling pathways. Dominant negative JAK2 (delta JAK2) lacking the C-terminus kinase domain, suppressed IL-3/GM-CSF induced c-fos activation, c-myc activation and proliferation suggesting that JAK2 is involved in both signaling pathways. PTP1D and Shc are phosphorylated by IL-3/GM-CSF in BA/F3 cells, however these phosphorylation events were inhibited by expression of delta JAK2. Taken together, these results indicate that JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP1D activation.
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PMID:Roles of JAK kinase in human GM-CSF receptor signals. 920 4

Uptake of L-[14C]glutamate (L-[14C]GLU) into nonsynaptic mitochondria isolated from rat cerebral hemispheres was measured in the presence of potential modulators of amino acid transport. The L-GLU carrier agonist 0.2 mM L-aspartate (L-ASP) virtually abolished L-GLU uptake (ASP/GLU concentration ratio, 1:1). L-Arginine (L-ARG) inhibited L-GLU uptake in a dose dependent manner over the concentration range 0.1-5 mM to maximum inhibition of 85%. Putrescine or ammonia had no effect, whereas 5 mM creatine and the NO generator, 5 mM sodium nitroprusside, increased the uptake by 73% and 57%, respectively. D-ARG was three times less effective in inhibiting L-GLU uptake than L-ARG at 5 mM concentration. The L-amino acids ornithine, lysine, histidine, tyrosine, phenylalanine, proline, leucine, isoleucine, tryptophan, glycine, methionine, valine, serine, taurine, alanine or cysteine did not affect the uptake when added in concentrations of 2-5 mM. A 14% inhibition of L-GLU uptake was noted in the presence of L-glutamine (L-GLN) (2 mM) or a dicarboxylate carrier ligand, alpha-ketoglutarate (alpha-KG) (5 mM), and a 30% inhibition with a dicarboxylate carrier inhibitor phenylsuccinate (PhSc) (5 mM). The results suggest that L-ARG functions as a specific endogenous modulator of cerebral mitochondrial L-GLU transport.
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PMID:Glutamate uptake is inhibited by L-arginine in mitochondria isolated from rat cerebrum. 924 41

The presence of a proteolytic activity in sera from pregnant humans and rodents capable of degrading insulin-like growth factor binding protein-3 (IGFBP-3) has been known for some time. However, the identity of this activity has remained elusive. We have attempted to purify the IGFBP-3 protease activity from pregnant human serum (PHS) using the degradation of 125I-IGFBP-3 as a marker. Following ammonium sulfate precipitation of PHS and further enrichment of active fractions by ion-exchange, protein-A Sepharose, and size-exclusion chromatography, a protease of approximately 70-90 kDa was isolated and subjected to N-terminal analysis. The N-terminal sequence was consistent with plasminogen, a known fibrinolytic enzyme. To further characterize the IGFBP-3 protease activities in both PHS and nonpregnant human serum (NHS), aliquots of serum were first enriched by polyethylene glycol-precipitation and subjected to size-exclusion chromatography. The size-separated fractions were then incubated with 125I-IGFBP-3, and proteolytic activity was measured. PHS contained two separate proteases (>150 kDa and 70-90 kDa), whereas NHS contained only one (70-90 kDa) that had a inhibitor profile similar to plasmin. However, inhibitors of plasmin had no effect on the activity of the >150-kDa protease. Plasminogen activators (PAs) greatly increased the activity of the 70- to 90-kDa protease, but had little effect on the >150-kDa protease activity. Addition of PAs greatly increased the ability of NHS to proteolyze IGFBP-3. In contrast, the ability of plasminogen-depleted plasma to degrade 125I-IGFBP-3 was not affected by the addition of PAs. Both urokinase and tissue-type PA had the ability to proteolyze IGFBP-3 and were, in contrast to the >150-kDa protease activity, inhibited by the specific PA inhibitor D-PHE-PRO-ARG chloromethyl ketone. The present data suggest that sera has the ability to proteolyze IGFBP-3, and that this ability, as demonstrated by NHS, can be regulated by protease inhibitors and PAs. In addition, PHS does indeed contain an unique IGFBP-3 protease activity that is not present in NHS, and its identity is unknown at this time.
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PMID:Human pregnancy serum contains at least two distinct proteolytic activities with the ability to degrade insulin-like growth factor binding protein-3. 927 81


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