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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage colony-stimulating factor (M-CSF) is required for the proliferation, differentiation, and activation of monocytes. High-affinity receptors for M-CSF are encoded by the c-fms proto-oncogene. In the present study, we show that c-fms transcripts are detectable in human THP-1 myeloid leukemia cells. Furthermore, radiolabeled 125I-M-CSF is rapidly internalized into THP-1 cells and then degraded intracellularly. The results also show that treatment of THP-1 cells with M-CSF is associated with the activation of protein kinase C (PKC) and the induction of tumor necrosis factor (TNF) gene expression. TNF transcript levels were low to undetectable in uninduced THP-1 cells, reached maximal levels by 1 hour of exposure to M-CSF, and returned to those of control cells by 24 hours. Transcriptional run-on analysis showed that a low level of TNF transcription is detectable in untreated THP-1 cells, and M-CSF treatment increased the rate of TNF transcription. Pretreatment of THP-1 cells with pertussis toxin inhibited the increase in PKC activity but not the induction of TNF transcripts by M-CSF. Moreover, exposure of THP-1 cells to inhibitors of protein kinase activity blocked the increase in TNF messenger RNA. These findings suggest that at least two M-CSF-mediated signaling pathways exist in THP-1 cells and that the induction of TNF may be regulated by a protein kinase-dependent mechanism distinct from PKC.
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PMID:Functional expression of the macrophage colony-stimulating factor receptor in human THP-1 monocytic leukemia cells. 153 7

We investigated the interaction of phospholipase C-gamma (PLC-gamma) with wild-type and mutant forms of the platelet-derived growth factor (PDGF) beta-receptor both in vivo and in vitro. After PDGF treatment of CHO cell lines expressing wild-type or either of two mutant (delta Ki and Y825F) PDGF receptors, PLC-gamma became tyrosine phosphorylated and associated with the receptor proteins. The receptor association and tyrosine phosphorylation of PLC-gamma correlated with the ability of these receptors to mediate ligand-induced phosphatidylinositol turnover. However, both the delta Ki and Y825F mutant receptors were deficient in transmitting mitogenic signals, suggesting that the PDGF-induced tyrosine phosphorylation and receptor association of PLC-gamma are not sufficient to account for the growth-stimulatory activity of PDGF. Wild-type and delta Ki mutant PDGF receptor proteins expressed with recombinant baculovirus vectors also associated in vitro with mammalian PLC-gamma. However, baculovirus-expressed c-fms, v-fms, c-src, and Raf-1 proteins failed to associate with PLC-gamma under similar conditions. Phosphatase treatment of the baculovirus-expressed PDGF receptor greatly decreased its association with PLC-gamma. This requirement for receptor phosphorylation was also observed in vivo, where PLC-gamma could not associate with a mutant PDGF receptor (K602A) defective in autophosphorylation. PLC-gamma also coimmunoprecipitated with two other putative receptor substrates, the serine-threonine kinase Raf-1 and the 85-kilodalton phosphatidylinositol-3' kinase, presumably through its association with the ligand-activated receptor. Furthermore, baculovirus-expressed Raf-1 phosphorylated purified PLC-gamma in vitro at sites which showed increased serine phosphorylation in vivo in response to PDGF. These results suggest that PDGF directly influences PLC activity by inducing the association of PLC-gamma with a receptor signaling complex, resulting in increased tyrosine and serine phosphorylation of PLC-gamma.
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PMID:Platelet-derived growth factor (PDGF)-dependent association of phospholipase C-gamma with the PDGF receptor signaling complex. 169 40

The proto-oncogene c-raf-1 encodes a 74 kD serine/threonine kinase. Recently, it has been shown that Raf kinase activity is stimulated by platelet derived growth factor (PDGF) treatment of receptor bearing cells, and that p74 is a direct substrate for PDGF receptor. CSF-1 treatment of BeWo cells, a human choriocarcinoma cell line, and mouse NIH 3T3 cells expressing a transfected human CSF-1 receptor cDNA, was associated with a 3-4 fold increase in phosphorylation of a 74 kD protein immunoprecipitated with affinity purified Raf-1 antibody. The kinase activity of p74 was increased 2-3 fold against two exogenous substrates following CSF-1 treatment of the transfected cells. These observations suggest that Raf-1 protein is a downstream second messenger molecule in CSF-1 mediated signal transduction.
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PMID:Human colony stimulating factor-1 receptor activates the C-raf-1 proto-oncogene kinase. 222 64

Phorbol esters induce the human HL-60 promyelocytic cell line to differentiate along a monocytic pathway. This induction of differentiation may involve phorbol ester-induced activation of the phospholipid- and calcium-dependent protein kinase C. Bryostatin 1, a macrocyclic lactone, has been shown to compete with phorbol esters for binding to protein kinase C. We have confirmed that bryostatin 1 translocates activity of protein kinase C from the cytosolic to membrane fractions of HL-60 cells. The present results also demonstrate that bryostatin 1 (10 nmol/L) induces monocytic differentiation of HL-60 cells as determined by adherence, growth inhibition, appearance of monocyte cell surface antigens, and alpha-naphthyl acetate esterase staining. Furthermore, bryostatin 1 (10 nmol/L) downregulated c-myc expression and induced c-fos, c-fms, and tumor necrosis factor transcripts. These changes in gene expression induced by bryostatin 1 are similar to those associated with phorbol ester-induced monocytic differentiation of HL-60 cells. In contrast, exposure to a higher concentration of bryostatin 1 (100 nmol/L) had less of an effect on growth inhibition of HL-60 cells and changes in gene expression. Moreover, 100 nmol/L bryostatin 1 antagonized the cytostatic effects and adherence induced by phorbol esters. Our results thus suggest that bryostatin 1 activates HL-60 cell protein kinase C and that this effect is associated with induction of monocytic differentiation.
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PMID:Bryostatin 1 activates protein kinase C and induces monocytic differentiation of HL-60 cells. 245 68

The protein kinase domains of v-kit, the oncogene of the acute transforming feline retrovirus HZ4-FeSV (HZ4-feline sarcoma virus), CSF-1R (macrophage colony stimulating factor receptor) and PDGFR (platelet derived growth factor receptor) display extensive homology. Because of the close structural relationship of v-kit, CSF-1R and PDGFR we predicted that c-kit would encode a protein kinase transmembrane receptor (Besmer et al., 1986a; Yarden et al., 1986). We have now determined the primary structure of murine c-kit from a DNA clone isolated from a brain cDNA library. The nucleotide sequence of the c-kit cDNA predicts a 975 amino acid protein product with a calculated mol. wt of 109.001 kd. It contains an N-terminal signal peptide, a transmembrane domain (residues 519-543) and in the C-terminal half the v-kit homologous sequences (residues 558-925). c-kit therefore contains the features which are characteristic of a transmembrane receptor kinase. Comparison of c-kit, CSF-1R and PDGFR revealed a unique structural relationship of these receptor kinases suggesting a common evolutionary origin. The outer cellular domain of c-kit was shown to be related to the immunoglobulin superfamily. The sites of expression of c-kit in normal tissue predict a function in the brain and in hematopoietic cells. N-terminal sequences which include the extracellular domain and the transmembrane domain as well as 50 amino acids from the C-terminus of c-kit are deleted in v-kit. These structural alterations are likely determinants of the oncogenic activation of v-kit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Primary structure of c-kit: relationship with the CSF-1/PDGF receptor kinase family--oncogenic activation of v-kit involves deletion of extracellular domain and C terminus. 245 20

The c-fms proto-oncogene is a member of a gene family that has been implicated in tumorigenesis. Glycoproteins encoded by c-fms were identified in cat spleen cells by means of an immune-complex kinase assay performed with monoclonal antibodies to v-fms-coded epitopes. The major form of the normal cellular glycoprotein has an apparent molecular weight of 170,000 and, like the product of the viral oncogene, serves as a substrate for an associated tyrosine-specific protein kinase activity in vitro. The results suggest that the transforming glycoprotein specified by v-fms is a truncated form of a c-fms-coded growth factor receptor.
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PMID:The product of the c-fms proto-oncogene: a glycoprotein with associated tyrosine kinase activity. 258 Mar 48

The protein encoded by v-fms, the oncogene of the Susan McDonough strain of feline sarcoma virus, is a member of the protein tyrosine kinase family. The kinase activity of the v-fms encoded protein has been reported to be low compared to other members of this enzyme family. We found that the optimal pH in vitro for the autophosphorylation of the immunoprecipitated v-fms encoded protein kinase activity was about pH 5.0; the activity at this pH was 15-fold higher than at the pH (7.4) used in standard kinase assays. The low pH optimum of the kinase activity of the v-fms encoded protein was observed when this protein was immunoprecipitated with each of four independent polyclonal antisera. v-fms proteins from transfected rat, mink or hamster cells all showed the same pH optimum for the kinase activity, as did the protein encoded by the feline c-fms gene. Autophosphorylation of v-fms in vitro at pH 5.0 occurred exclusively on tyrosine residues. Enolase was a substrate for the v-fms encoded protein kinase, and the pH profile for phosphorylation of this substrate in vitro paralleled that seen for the autophosphorylation of v-fms encoded proteins. The discovery of the low pH optimum of the kinase activity exhibited by v-fms proteins may be useful for further characterization of this activity in vitro, as well as for phenotypic classification of other members of the protein tyrosine kinase family.
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PMID:The kinase activity of the v-fms encoded protein has a low pH optimum. 265 15

The c-fms proto-oncogene product is a transmembrane glycoprotein that is probably identical to the cell surface receptor for the mononuclear phagocyte colony stimulating factor, CSF-1. An analogous glycoprotein encoded by the viral oncogene v-fms includes the extracellular ligand-binding domain, membrane spanning segment, and cytoplasmic tyrosine kinase domain of the CSF-1 receptor. The v-fms and c-fms gene products differ significantly at their distal carboxylterminal ends where the truncated viral transforming protein has lost a single tyrosine residue (tyr969) that may negatively regulate the receptor kinase activity. Introduction of v-fms into a CSF-1 dependent murine macrophage cell line induced factor independence and tumorigenicity by a nonautocrine mechanism. Thus, although the v-fms gene product can bind CSF-1, its constitutive tyrosine-specific protein kinase provides growth stimulatory signals in the absence of ligand. Transfection of human c-fms cDNA into mouse NIH-3T3 cells conferred a CSF-1 responsive phenotype. Although neither the wild-type c-fms (tyr969) gene nor a mutant c-fms (phe969) allele induced transformation of NIH-3T3 cells, cotransfection with human CSF-1 cDNA gave rise to transformed foci. In cells cotransfected with the CSF-1 gene, the efficiency of focus formation induced by the mutant c-fms (phe969) gene was greater than that of the wild-type gene and equivalent to that of v-fms alone. A chimeric v-fms/c-fms molecule in which the carboxylterminus of the v-fms gene product was replaced by the corresponding region of the wild type c-fms (tyr969) was weakly transforming, whereas chimeric molecules containing phe969 transformed NIH-3T3 cells efficiently. Thus, complete oncogenic activation of the c-fms gene appears to require two events: one which alters a putative negative regulatory site of tyrosine phosphorylation, and a second which phenocopies a ligand-induced conformational change.
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PMID:Requirements for transformation by the fms oncogene product (CSF-1 receptor). 284 95

The macrophage colony-stimulating factor, CSF-1 (M-CSF), is a homodimeric glycoprotein required for the lineage-specific growth of cells of the mononuclear phagocyte series. Apart from its role in stimulating the proliferation of bone marrow-derived precursors of monocytes and macrophages, CSF-1 acts as a survival factor and primes mature macrophages to carry out differentiated functions. Each of the actions of CSF-1 are mediated through its binding to a single class of high-affinity receptors expressed on monocytes, macrophages, and their committed progenitors. The CSF-1 receptor (CSF-1R) is encoded by the c-fms proto-oncogene, and is one of a family of growth factor receptors that exhibits an intrinsic tyrosine-specific protein kinase activity. Transduction of c-fms sequences as a viral oncogene (v-fms) in the McDonough (SM) and HZ-5 strains of feline sarcoma virus has resulted in alterations in receptor coding sequences that affect its activity as a tyrosine kinase and provide persistent signals for cell growth in the absence of its ligand. The genetic alterations in the c-fms gene that unmask its latent transforming potential abrogate its lineage-specific activity and enable v-fms to transform a variety of cells that do not normally express CSF-1 receptors.
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PMID:Colony-stimulating factor-1 receptor (c-fms). 285 67

Alterations in genes that function in normal growth and development have been linked to malignant cell transformation. The mononuclear phagocyte colony-stimulating factor (CSF-1 or M-CSF) is a polypeptide growth factor synthesized by mesenchymal cells, which stimulates the survival, proliferation, and differentiation of haematopoietic cells of the monocyte-macrophage series. Multiple forms of soluble CSF-1 are produced by proteolytic cleavage of membrane-bound precursors, some of which are stably expressed at the cell surface. The c-fms proto-oncogene encodes the CSF-1 receptor, which is composed of an extracellular ligand-binding domain linked by a single membrane-spanning segment to a cytoplasmic tyrosine-specific protein kinase domain. Whereas the tyrosine kinase activity of the normal receptor is stimulated by CSF-1, mutations in the c-fms gene can constitutively activate the kinase to provide growth-stimulatory signals in the absence of the ligand. Oncogenic activation of the c-fms gene product appears to involve removal of a negative regulatory tyrosine residue near the carboxyl terminus of the receptor and one or more additional mutations that may simulate a conformational change induced by CSF-1 binding. Expression of the human c-fms gene in mouse NIH-3T3 cells confers a CSF-1 stimulated growth phenotype, indicating that receptor transduction is sufficient for fibroblasts to respond to a haematopoietic growth factor. In contrast, the v-fms oncogene induces factor-independent growth and tumorigenicity in factor-dependent myeloid cell lines, and contributes to the development of proliferative disorders of multiple haematopoietic lineages when introduced into murine bone marrow progenitors. Aberrant expression of an endogenous c-fms gene secondary to proviral insertion and transcriptional activation has also been implicated in virus-induced myeloblastic leukaemia in mice. The c-fms and CSF-1 genes have been mapped on the long arm of human chromosome 5, a region that frequently undergoes interstitial deletions in certain haematopoietic disorders including acute myelogenous leukaemia. The study of CSF-1 and its receptor should provide information concerning the role of tyrosine kinases in regulating the normal growth and differentiation of haematopoietic cells and in contributing to their malignant transformation.
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PMID:The colony-stimulating factor 1 (CSF-1) receptor (c-fms proto-oncogene product) and its ligand. 297 16


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