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J. Biol. Chem., Vol. 281, Issue 39, 28615-28626, September 29, 2006

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

Min Yu¹, Jincai Luo¹², Wentian Yang, Yongping Wang, Masao Mizuki³, Yuzuru Kanakura³, Peter Besmer^¶, Benjamin G. Neel, and Haihua Gu⁴

From the Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, the Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan, and the ^¶Developmental Biology Program, Sloan-Kettering Institute, New York, New York 10021

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.

Received for publication, April 19, 2006 , and in revised form, June 21, 2006.

^* This work was supported in part by Grants NIH R01-AI51612 (to H. G.), DK50693 (to B. G. N.), and HL/DK55748 (to P. B.) from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Present address: Inst. of Molecular Medicine, Peking University, New Life Sciences Building, Room 238, Mail Box 135, 5 Yiheyuan Rd., Beijing 100871, China.

³ Supported by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and Japan Society for the Promotion of Science.

⁴ A recipient of the Junior Faculty Scholar Award from American Association of Hematology. To whom correspondence should be addressed: NRB 1030N, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-667-0908; Fax: 617-667-0610; E-mail: hgu{at}bidmc.harvard.edu.

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