Gab proteins amplify and integrate signals stimulated by many growth factors. In culture and animals, retinoic acid (RA) induces neuronal differentiation. We show that Gab2 expression is detected in neurons in three models of neuronal differentiation: embryonic carcinoma (EC) stem cells, embryonic stem cells, and primary neural stem cells (NSCs). RA treatment induces apoptosis, countered by basic FGF (bFGF). In EC cells, Gab2 silencing results in hypersensitivity to RA-induced apoptosis and abrogates the protection by bFGF. Gab2 suppression reduces bFGF-dependent activation of AKT but not ERK, and constitutively active AKT, but not constitutively active MEK1, reverses the hypersensitization. Thus, Gab2-mediated AKT activation is required for bFGF's protection. Moreover, Gab2 silencing impairs the differentiation of EC cells to neurons. Similarly, in NSCs, Gab2 suppression reduces bFGF-dependent proliferation as well as neuronal survival and production upon differentiation. Our findings provide the first evidence that Gab2 is an important player in neural differentiation, partly by acting downstream of bFGF to mediate survival through phosphoinositide 3 kinase–AKT.
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18 July 2005
Article|
July 11 2005
A novel role for Gab2 in bFGF-mediated cell survival during retinoic acid–induced neuronal differentiation
Yingwei Mao,
Yingwei Mao
Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI 48105
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Angel W.-M. Lee
Angel W.-M. Lee
Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI 48105
Search for other works by this author on:
Yingwei Mao
Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI 48105
Angel W.-M. Lee
Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI 48105
Correspondence to Angel W.-M. Lee: [email protected]
Abbreviations used in this paper: AlexaFluor, AF; bFGF, basic FGF; EC, embryonic carcinoma; ES, embryonic stem; FGFR, FGF receptor; GFAP, glial fibrillary acidic protein; LY, LY294002; NSC, neural stem cell; PH, pleckstrin homology; PI3K, phosphoinositide 3 kinase; PIP3, phosphatidylinositol-3,4,5-P3; PY, phosphotyrosine; RA, retinoic acid; shRNA, small hairpin RNA; SVZ, subventricular zone; WT, wild type.
Received:
May 10 2005
Accepted:
June 15 2005
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2005
J Cell Biol (2005) 170 (2): 305–316.
Article history
Received:
May 10 2005
Accepted:
June 15 2005
Citation
Yingwei Mao, Angel W.-M. Lee; A novel role for Gab2 in bFGF-mediated cell survival during retinoic acid–induced neuronal differentiation . J Cell Biol 18 July 2005; 170 (2): 305–316. doi: https://doi.org/10.1083/jcb.200505061
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