The Scaffolding Adapter Gab2, via Shp-2, Regulates Kit-evoked Mast Cell Proliferation by Activating the Rac/JNK Pathway

• Published in: The Journal of biological chemistry 2006-09, Vol.281 (39), p.28615-28626
• Main Authors: Yu, Min, Luo, Jincai, Yang, Wentian, Wang, Yongping, Mizuki, Masao, Kanakura, Yuzuru, Besmer, Peter, Neel, Benjamin G., Gu, Haihua
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Cell Proliferation; Intracellular Signaling Peptides and Proteins - physiology; MAP Kinase Kinase 4 - metabolism; MAP Kinase Kinase 4 - physiology; Mast Cells - cytology; Mast Cells - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - physiology; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases - physiology; Proto-Oncogene Proteins c-kit - physiology; rac GTP-Binding Proteins - metabolism; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M603742200

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 Tyr567 and Tyr719, 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 Tyr567 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. Tyr567, 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 Tyr719, regulates mast cell proliferation and development in specific tissues. Our data show that Gab2 via Shp-2 is critical for transmitting signals from Kit Tyr567 to activate the Rac/JNK pathway controlling mast cell proliferation, which likely contributes to mast cell development in specific tissues.