title: Kit signal transduction.
abstract: The current understanding of kit signaling is that a limited number of signaling proteins interact to build multiple interacting networks that allow diverse cellular responses. Cytoplasmic signaling proteins are increasingly seen to form networks directed through converging and interacting pathways rather than following a simple linear model. There are also numerous cross-connections between signaling proteins more distal to the receptor. Ras thus binds PI3 kinase and potentiates its activation, whereas the Rac-dependent protein kinase PAK phosphorylates MEK and thereby stabilizes its association with Raf. A signaling network with multiple intersecting pathways can obtain a single, coherent response from numerous, potentially conflicting signals. There is still limited information about the effect of activating mutations on various aspects of kit signaling. There is, however, mounting evidence that an activating mutation may enhance kit signaling and also induce factor-independent activation of kit. For instance, this activation could occur through degradation of SHP-1, the protein tyrosine phosphatase that negatively regulates kit signaling. There is also emerging evidence that inherent inhibitory factors may exist in the juxtamembrane of kit and may be suppressed as a result of a mutation in that region. Understanding the impact of these activating mutations on kit signaling is important, not only in contributing to the understanding of the pathogenesis of mastocytosis but ultimately in forming the basis for more effective therapeutic intervention in this disease.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Taylor
authors.forename: D D
authors.initials: DD
authors.lastname: Metcalfe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution; D000818:Animals; D018797:Cell Cycle Proteins; D019281:Dimerization; D005246:Feedback; D051380:GRB2 Adaptor Protein; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D017354:Point Mutation; D011493:Protein Kinase C / Q000502:physiology; D011499:Protein Processing, Post-Translational; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D011506:Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D011519:Proto-Oncogenes; D019089:Stem Cell Factor / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology; D018909:src Homology Domains; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D007527:Isoenzymes; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D019089:Stem Cell Factor; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D019061:src-Family Kinases; D011493:Protein Kinase C; D017027:Protein Tyrosine Phosphatases; D018631:ras Proteins