Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kit receptor tyrosine kinase and erythropoietin receptor (Epo-R) cooperate in regulating blood cell development. Mice that lack the expression of Kit or Epo-R die in utero of severe anemia. Stimulation of Kit by its ligand, stem cell factor activates several distinct early signaling pathways, including phospholipase C gamma, phosphatidylinositol 3-kinase, Src kinase, Grb2, and Grb7. The role of these pathways in Kit-induced growth, proliferation, or cooperation with Epo-R is not known. We demonstrate that inactivation of any one of these early signaling pathways in Kit significantly impairs growth and proliferation. However, inactivation of the Src pathway demonstrated the most profound defect. Combined stimulation with Epo also resulted in impaired cooperation between Src-defective Kit mutant and Epo-R and, to a lesser extent, with Kit mutants defective in the activation of phosphatidylinositol 3-kinase or Grb2. The impaired cooperation between the Src-defective Kit mutant and Epo-R was associated with reduced transphosphorylation of Epo-R and expression of c-Myc. Remarkably, restoration of only the Src pathway in a Kit receptor defective in the activation of all early signaling pathways demonstrated a 50% correction in proliferation in response to Kit stimulation and completely restored the cooperation with Epo-R. These data demonstrate an essential role for Src pathway in regulating growth, proliferation, and cooperation with Epo-R downstream from Kit.
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PMID:Functional and biochemical consequences of abrogating the activation of multiple diverse early signaling pathways in Kit. Role for Src kinase pathway in Kit-induced cooperation with erythropoietin receptor. 1248 28

This work aims to elucidate the mechanisms involved in the early activation of glucose transport in hematopoietic M07e cells by stem cell factor (SCF) and a reactive oxygen species (ROS) as H2O2. SCF and H2O2 increase Vmax for glucose transport; this enhancement is due to a higher content in GLUT1 in plasma membranes, possibly through a translocation from intracellular stores. Inhibitors of tyrosine kinases or phospholipase C (PLC) remove glucose transport enhancement and prevent translocation. The inhibitory effect of STI-571 suggests a role for c-kit tyrosine kinase on glucose transport activation not only by SCF, but also by H2O2. On the other hand, neither protein kinase C nor phosphoinositide-3-kinase appear to be involved in the acute activation of glucose transport. Our data suggest that i) in M07e cells, SCF and exogenous H2O2 elicit a short-term activation of glucose transport through a translocation of GLUT1 from intracellular stores to plasma membranes; ii) both stimuli could share at least some signaling pathways leading to glucose uptake activation, involving protein tyrosine kinases and PLC iii) H2O2 could act increasing the level of tyrosine phosphorylation through the inhibition of tyrosine phosphatases and mimicking the regulation role of endogenous ROS.
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PMID:Stem cell factor and H2O2 induce GLUT1 translocation in M07e cells. 1532 33

Stem cell factor (SCF), the ligand of the c-Kit receptor, is expressed by various structural and inflammatory cells in the airways. Binding of SCF to c-Kit leads to activation of multiple pathways, including phosphatidyl-inositol-3 (PI3)-kinase, phospholipase C (PLC)-gamma, Src kinase, Janus kinase (JAK)/Signal Transducers and Activators of Transcription (STAT) and mitogen activated protein (MAP) kinase pathways. SCF is an important growth factor for mast cells, promoting their generation from CD34+ progenitor cells. In vitro, SCF induces mast cells survival, adhesion to extracellular matrix and degranulation, leading to expression and release of histamine, pro-inflammatory cytokines and chemokines. SCF also induces eosinophil adhesion and activation. SCF is upregulated in inflammatory conditions both in vitro and in vivo, in human and mice. Inhibition of the SCF/c-Kit pathway leads to significant decrease of histamine levels, mast cells and eosinophil infiltration, interleukin (IL)-4 production and airway hyperresponsiveness in vivo. Taken together, these data suggest that SCF/c-Kit may be a potential therapeutic target for the control of mast cell and eosinophil number and activation in inflammatory diseases.
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PMID:Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. 1648 68

We have previously shown that ectopic expression of metabotropic glutamate receptor subtype 1 in melanocytes is essential for both development and in vivo growth of melanoma using newly developed transgenic mice which conditionally express metabotropic glutamate receptor subtype 1 (mGluR1). In this study, we developed conditional transgenic mice, which harbor melanocytes not only in the dermis and hair follicles but also in the epidermis using stem cell factor transgenic mice. Pigmented plaques on the backs, tails, ears or groins of the transgenic mice began to appear 13 weeks after activation of the mGluR1 transgene, and the transgenic mice produced melanomas at a frequency of 100% 36 weeks after transgene activation. Although this transgenic mouse harbors melanocytes in the epidermis, proliferation of melanoma cells took place in the dermis. To elucidate the signals involved in development and growth of melanoma, inhibitors to phospholipase C, protein kinase C and mitogen-activated protein kinase kinase 1/2, and antagonists to Ca(2+) and calmodulin were administrated to transgenic mice. Each signal inhibitor to phospholipase, protein kinase C, Ca(2+) release, calmodulin and mitogen-activated protein kinase kinase 1/2 inhibited melanoma development. However, once melanoma was developed, the growth of melanoma was dramatically inhibited only by the inhibitor to mitogen-activated protein kinase kinase 1/2 with partial inhibition by inhibitors to protein kinase C and phospholipase C. This inhibition of melanoma growth was well correlated with the expression of phosphorylated extracellular signal-regulated kinase 1/2 and Ki-67. These results indicate that for development of melanoma, activation of every signaling pathway from mGluR1 is required. However, for growth of melanoma, the extracellular signal-regulated kinase pathway plays a key role.
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PMID:Pharmacogenomics of metabotropic glutamate receptor subtype 1 and in vivo malignant melanoma formation. 2062 30


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