The scaffolding adapter Gab2, via Shp-2, regulates Kit-evoked mast cell proliferation by activating the Rac/JNK pathway Journal Article

Authors: Yu, M.; Luo, J.; Yang, W.; Wang, Y.; Mizuki, M.; Kanakura, Y.; Besmer, P.; Neel, B. G.; Gu, H.
Article Title: The scaffolding adapter Gab2, via Shp-2, regulates Kit-evoked mast cell proliferation by activating the Rac/JNK pathway
Abstract: The scaffolding adapter Gab2 mediates cell signaling and responses evoked by various extracellular stimuli including several growth factors. Kit, the receptor for stem cell factor (SCF), plays a critical role in the proliferation and differentiation of a variety of cell types, including mast cells. Kit, via Tyr 567 and Tyr 719, activates Src family kinases (SFK) and PI3K respectively, which converge on the activation of a Rac/JNK pathway required for mast cell proliferation. However, how Kit Tyr 567 signals to Rac/JNK is not well understood. By analyzing Gab2 -/- mast cells, we find that Gab2 is required for SCF-evoked proliferation, activation of Rac/JNK, and Ras. Upon Kit activation in wild-type mast cells, Gab2 becomes tyrosyl-phosphorylated and associates with Kit and Shp-2. Tyr 567, an SFK binding site in Kit, and SFK activity were required for Gab2 tyrosyl phosphorylation and association with Shp-2. By re-expressing Gab2 or a Gab2 mutant that cannot bind Shp-2 in Gab2 -/- mast cells or acutely by deleting Shp-2 in mast cells, we found that Gab2 requires Shp-2 for SCF-evoked Rac/JNK, Ras activation, and mast cell proliferation. Lastly, by analyzing mast cells from mice with compound Gab2 and Kit Y719F mutations (i.e.,Gab2 -/-: KitY719F/Y719F mice), we find that Gab2, acting in a parallel pathway to PI3K from Kit Tyr 719, regulates mast cell proliferation and development in specific tissues. Our data show that Gab2 via Shp-2 is critical for transmitting signals from Kit Tyr 567 to activate the Rac/JNK pathway controlling mast cell proliferation, which likely contributes to mast cell development in specific tissues. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Keywords: signal transduction; unclassified drug; nonhuman; cell proliferation; proteins; animal cell; mouse; animals; mice; proto-oncogene proteins c-kit; apoptosis; cell maturation; protein; cell differentiation; phosphorylation; mice, inbred c57bl; mice, transgenic; intracellular signaling peptides and proteins; 1-phosphatidylinositol 3-kinase; phosphoproteins; binding site; mutagenesis; protein tyrosine phosphatase shp 2; tissue; rac protein; phosphorus; cells; mast cell; mast cells; map kinase kinase 4; rac gtp-binding proteins; phosphatidylinositol 3-kinases; activation analysis; protein-tyrosine-phosphatase; scaffolds; mast cell development; stem cell factor (scf); protein gab2; protein tyrosine phosphatase, non-receptor type 11; protein tyrosine phosphatases
Journal Title: Journal of Biological Chemistry
Volume: 281
Issue: 39
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2006-09-29
Start Page: 28615
End Page: 28626
Language: English
DOI: 10.1074/jbc.M603742200
PUBMED: 16873377
PROVIDER: scopus
Notes: --- - "Export Date: 4 June 2012" - "CODEN: JBCHA" - "Source: Scopus"
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MSK Authors
  1. Peter Besmer
    105 Besmer