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)

A link between ABL oncogenes and MYC is suggested by the transformation synergy that is observed when MYC is expressed at high levels. Dominant negative MYC proteins were overexpressed in fibroblasts to determine if MYC complements ABL oncogene transformation or is essential for this process. Transformation by both v-abl and BCR-ABL oncogenes was reduced 5- to 10-fold, whereas transformation by the serine/threonine kinase oncogene v-mos was unaffected. Using a retrovirus construct modified to express BCR-ABL and MYC genes simultaneously, we show that dominant negative MYC suppressed transformation of primary mouse bone marrow pre-B cells by BCR-ABL. These observations demonstrate that c-MYC is essential for transformation and help define the pathway by which these proteins cause transformation.
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PMID:Dominant negative MYC blocks transformation by ABL oncogenes. 152 28

Sequences encoded by the first exon of BCR that bind to the ABL SH2 domain are essential for the activation of the ABL tyrosine kinase and transforming potential of the chimeric BCR-ABL oncogene. The normal cellular BCR gene encodes a 160,000 dalton phosphoprotein associated with a serine/threonine kinase activity, but it shows only weak dispersed homologies to protein kinases. p160c-BCR was purified to apparent homogeneity as an oligomer of greater than 600,000 daltons that contains autophosphorylation activity and transphosphorylation activity for several protein substrates. A region containing paired cysteine residues within the 426 amino acids encoded by the first exon of BCR is essential for its novel phosphotransferase activity, which overlaps with the strong SH2-binding regions. The recent demonstration of a GTPase-activating function within the C-terminal portion of BCR suggests that the protein kinase and SH2-binding domains may work in concert with other regions of the molecule in intracellular signalling processes.
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PMID:The BCR gene encodes a novel serine/threonine kinase activity within a single exon. 165 98

The human bcr gene encodes a protein with serine/threonine kinase activity, CDC24/dbl homology, a GAP domain, and an SH2-binding region. However, the precise physiological functions of BCR are unknown. Coexpression of BCR with the cytoplasmic protein-tyrosine kinase encoded by the c-fes proto-oncogene in Sf-9 cells resulted in stable BCR-FES protein complex formation and tyrosine phosphorylation of BCR. Association involves the SH2 domain of FES and a novel binding domain localized to the first 347 amino acids of the FES N-terminal region. Deletion of the homologous N-terminal BCR-binding domain from v-fps, a fes-related transforming oncogene, abolished transforming activity and tyrosine phosphorylation of BCR in vivo. Tyrosine phosphorylation of BCR in v-fps-transformed cells induced its association with GRB-2/SOS, the RAS guanine nucleotide exchange factor complex. These data provide evidence that BCR couples the cytoplasmic protein-tyrosine kinase and RAS signaling pathways.
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PMID:Tyrosine phosphorylation of BCR by FPS/FES protein-tyrosine kinases induces association of BCR with GRB-2/SOS. 752 74

Identification of the signal transduction pathways used by PRL is essential for understanding the role of PRL receptors in growth and differentiation processes. Early cellular mediators of PRL receptor activation include tyrosine kinases of the Janus kinase (JAK) and SRC families, with rapid nuclear signaling via tyrosine phosphorylated signal transducers and activators of transcription. In the present study we provide the first demonstration of PRL-induced activation of Ras, an oncogenic protein that supports an alternative signaling route from the membrane to the nucleus. PRL stimulated Ras in rat Nb2-SP lymphoma cells, as detected by a 2.0-fold increase in the GTP-bound state of the molecule (P < 0.01). This activation was associated with marked tyrosine phosphorylation and increased membrane association of the 52-kilodalton form of SHC. Moreover, PRL induced binding of SHC to growth factor receptor bound 2 and the guanine-nucleotide exchange factor son of sevenless, a common method used by growth factor receptors to activate Ras. In contrast, no apparent regulation by PRL of Ras via VAV or p120 Ras-guanosine triphosphatase-activating protein was detected, based upon an absence of PRL-inducible tyrosine phosphorylation of these proteins. Collectively, these results provide a molecular bridge between activation of PRL receptor-associated tyrosine kinases and subsequent stimulation of the serine/threonine kinase Raf-1, an established Ras target that was recently shown to be activated by PRL in Nb2 cells. We conclude that PRL is able to activate Ras via recruitment of the signaling proteins SHC, growth factor receptor bound 2, and son of sevenless in Nb2 cells. Moreover, PRL induced tyrosine phosphorylation of SHC in two of three PRL-responsive human breast cancer cell lines, suggesting that SHC-mediated Ras activation is a commonly used signaling strategy by PRL.
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PMID:Prolactin activates Ras via signaling proteins SHC, growth factor receptor bound 2, and son of sevenless. 762 88

Bone morphogenetic proteins (BMPs) comprise the largest subfamily of TGF-beta-related ligands and are known to bind to type I and type II receptor serine/threonine kinases. Although several mammalian BMP type I receptors have been identified, the mammalian BMP type II receptors have remained elusive. We have isolated a cDNA encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type II receptor that binds BMP-4. This receptor (BRK-3) is distantly related to other known type II receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain. The BRK-3 gene is widely expressed in a variety of adult tissues. When expressed alone in COS cells, BRK-3 specifically binds BMP-4, but cross-linking of BMP-4 to BRK-3 is undetectable in the absence of either the BRK-1 or BRK-2 BMP type I receptors. Cotransfection of BRK-2 with BRK-3 greatly enhanced affinity labeling of BMP-4 to the type I receptor, in contrast to the affinity labeling pattern observed with the BRK-1 + BRK-3 heteromeric complex. Furthermore, a subpopulation of super-high affinity binding sites is formed in COS cells upon cotransfection only of BRK-2 + BRK-3, suggesting that the different heteromeric BMP receptor complexes have different signaling potential.
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PMID:Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors. 767 43

The bone morphogenetic proteins (BMPs) are a group of transforming growth factor beta (TGF-beta)-related factors whose only receptor identified to date is the product of the daf-4 gene from Caenorhabditis elegans. Mouse embryonic NIH 3T3 fibroblasts display high-affinity 125I-BMP-4 binding sites. Binding assays are not possible with the isoform 125I-BMP-2 unless the positively charged N-terminal sequence is removed to create a modified BMP-2, 125I-DR-BMP-2. Cross-competition experiments reveal that BMP-2 and BMP-4 interact with the same binding sites. Affinity cross-linking assays show that both BMPs interact with cell surface proteins corresponding in size to the type I (57- to 62-kDa) and type II (75- to 82-kDa) receptor components for TGF-beta and activin. Using a PCR approach, we have cloned a cDNA from NIH 3T3 cells which encodes a novel member of the transmembrane serine/threonine kinase family most closely resembling the cloned type I receptors for TGF-beta and activin. Transient expression of this receptor in COS-7 cells leads to an increase in specific 125I-BMP-4 binding and the appearance of a major affinity-labeled product of approximately 64 kDa that can be labeled by either tracer. This receptor has been named BRK-1 in recognition of its ability to bind BMP-2 and BMP-4 and its receptor kinase structure. Although BRK-1 does not require cotransfection of a type II receptor in order to bind ligand in COS cells, complex formation between BRK-1 and the BMP type II receptor DAF-4 can be demonstrated when the two receptors are coexpressed, affinity labeled, and immunoprecipitated with antibodies to either receptor subunit. We conclude that BRK-1 is a putative BMP type I receptor capable of interacting with a known type II receptor for BMPs.
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PMID:Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. 806 29

Protein kinase play important roles in the growth and differentiation of cells. We have isolated cDNA clones from the human megakaryocytic cell line CMK11-5 that encode a novel protein kinase, which we call SPRK (src-homology 3 (SH3) domain-containing proline-rich kinase). The gene sequence predicts an 847-amino acid protein kinase with a unique domain arrangement. An amino-terminal glycine-rich region is followed by an SH3 domain and a kinase domain that is similar to both tyrosine and serine/threonine kinases. Adjacent to the kinase domain are two closely spaced leucine/isoleucine zipper motifs and a stretch of basic amino acids that resembles karyophilic nuclear localization signals. The COOH-terminal half of SPRK is basic, and proline accounts for 24% of the COOH-terminal 216 amino acids. The sprk gene is widely expressed as a 4-kilobase transcript in adult and fetal human tissues. Transfection of 293 cells with a vector encoding an epitope-tagged SPRK results in the expression of a 95-kDa protein. The epitope-tagged SPRK becomes phosphorylated on serine and threonine residues in an in vitro kinase assay, whereas SPRK variants with point mutations in the predicted ATP-binding site fail to become phosphorylated. These data indicate that SPRK has serine/threonine kinase activity. The SH3 domain of SPRK is interrupted by a unique 5-amino acid insert whose location in the SH3 consensus sequence is the same as that of the inserts found in the SH3 domains of neuronal SRC and of the p85 subunit of phosphatidylinositol 3-kinase.
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PMID:Identification and characterization of SPRK, a novel src-homology 3 domain-containing proline-rich kinase with serine/threonine kinase activity. 819 46

The first exon of the BCR gene encodes a new serine/threonine protein kinase. Abnormal fusion of the BCR and ABL genes, resulting from the formation of the Philadelphia chromosome (Ph), is the hallmark of Ph-positive leukemia. We have previously demonstrated that the Bcr protein is tyrosine phosphorylated within first-exon sequences by the Bcr-Abl oncoprotein. Here we report that in addition to tyrose 177 (Y-177), Y-360 and Y283 are phosphorylated in Bcr-Abl proteins in vitro. Moreover, Bcr tyrosine 360 is phosphorylated in vivo within both Bcr-Abl and Bcr. Bcr mutant Y177F had a greatly reduced ability to transphosphorylate casein and histone H1, whereas Bcr mutants Y177F and Y283F had wild-type activities. In contrast, the Y360F mutation had little effect on Bcr's autophosphorylation activity. Tyrosine-phosphorylated Bcr, phosphorylated in vitro by Bcr-Abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of Bcr. Similarly, the isolation of Bcr from cells expressing Bcr-Abl under conditions that preserve phosphotyrosine residues also reduced Bcr's kinase activity. These results indicate that tyrosine 360 of Bcr is critical for the transphosphorylation activity of Bcr and that in Ph-positive leukemia, Bcr serine/threonine kinase activity is seriously impaired.
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PMID:Inhibition of Bcr serine kinase by tyrosine phosphorylation. 862 3

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

Serum and certain growth factors have the ability to inhibit programmed cell death (apoptosis) and promote survival. The mechanism by which growth factors deliver an anti-apoptotic signal and the mechanism by which this survival signal is uncoupled from mitogenesis are not clear. We studied five downstream effectors of growth factor receptors--Ras, Raf, Src, phosphoinositide 3-kinase (PI 3-kinase), and Akt (PKB)--for their abilities to block apoptosis. Activated forms of Ras, Raf, and Src, although transforming, were not sufficient to deliver a survival signal upon serum withdrawal. In contrast, inhibition of PI 3-kinase accelerated apoptosis, and an activated form of the serine/threonine kinase Akt, a downstream effector of PI 3-kinase, blocked apoptosis. The ability of Akt to promote survival was dependent on and proportional to its kinase activity. In Rat1a fibroblasts, activated Akt did not alter Bcl-2 or Bcl-X(L) expression but inhibited Ced3/ICE-like activity. Thus, the PI 3-kinase/Akt (PKB) signaling pathway transduces a survival signal that ultimately blocks Ced3/ICE-like activity. These results suggest that uncoupling of survival and mitogenesis can be explained by differing abilities of distinct mitogens to efficiently induce the PI 3-kinase/Akt signaling pathway.
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PMID:The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. 908 25


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