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Molecular and Cellular Biology, June 2006, p. 4664-4674, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.02253-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Concerted Functions of Gab1 and Shp2 in Liver Regeneration and Hepatoprotection

Emilie A. Bard-Chapeau,1 Jing Yuan,1 Nathalie Droin,3 Shinong Long,1 Eric E. Zhang,1,2 Thanh V. Nguyen,1 and Gen-Sheng Feng1,2*

Programs in Signal Transduction and Stem Cells and Regeneration, The Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, California 92037,1 Department of Pathology, University of California at San Diego, La Jolla, California 92093,2 Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 921213

Received 22 November 2005/ Returned for modification 12 January 2006/ Accepted 5 April 2006

Liver regeneration is a rapid and concerted response to injury, in which growth factor-generated intracellular signals result in activation of transcription factors, DNA synthesis, and hepatocyte proliferation. However, the link between cytoplasmic signals resulting in proliferative response to liver injury remains to be elucidated. We show here that association of Gab1 adaptor protein and Shp2 tyrosine phosphatase is a critical event at the early phase of liver regeneration. Partial hepatectomy (PH) rapidly and transiently induced assembly of a complex comprising Shp2 and tyrosine-phosphorylated Gab1 in wild-type hepatocytes. Consistently, liver-specific Shp2 knockout (LSKO) and liver-specific Gab1 knockout (LGKO) mice displayed very similar phenotypes of defective liver regeneration triggered by PH, including blunted extracellular signal-regulated kinase 1/2 (Erk1/2) activation, decreased expression of immediate-early genes, and reduced levels of cyclins A, E, and B1, as well as suppression of hepatocyte proliferation. In contrast, the Akt and interleukin-6/Stat3 pathways were up-regulated posthepatectomy in LSKO and LGKO mice, accompanied by improved hepatoprotection. Collectively, this study establishes the physiological significance of the Gab1/Shp2 link in promoting mitogenic signaling through the Erk pathway in mammalian liver regeneration.

* Corresponding author. Mailing address: The Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 713-6265. Fax: (858) 713-6274. E-mail: gfeng{at}burnham.org.

Molecular and Cellular Biology, June 2006, p. 4664-4674, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.02253-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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