The protein-tyrosine phosphatase SHP-2 is required during angiotensin II-mediated activation of cyclin D1 promoter in CHO-AT(1A) cells

Angiotensin II (Ang II) binds to specific G protein-coupled receptors and i s mitogenic in Chinese hamster ovary (CHO) cells stably expressing a rat va scular angiotensin II type LA receptor (CHO-AT(1A)). Cyclin D1 protein expr ession is regulated by mitogens, and its assembly with the cyclin-dependent kinases induces phosphorylation of the retinoblastoma protein pRb, a criti cal step in G(1) to S phase cell cycle progression contributing to the prol iferative responses. In the present study, we found that in CHO-AT(1A) cell s, Ang II induced a rapid and reversible tyrosine phosphorylation of variou s intracellular proteins including the protein-tyrosine phosphatase SHP-2. Ang II also induced cyclin D1 protein expression in a phosphatidylinositol 3-kinase and mitogen-activated protein kinase/extracellular signal-regulate d kinase (MAPK/ERK)-dependent manner. Using a pharmacological and a co-tran sfection approach, we found that p21(ras), Raf-1, phosphatidylinositol 3-ki nase and also the catalytic activity of SHP-2 and its Src homology 2 domain s are required for cyclin D1 promoter/reporter gene activation by Ang II th rough the regulation of MAPK/ERK activity. Our findings suggest for the fir st time that SHP-2 could play an important role in the regulation of a gene involved in the control of cell cycle progression resulting from stimulati on of a G protein-coupled receptor independently of epidermal growth factor receptor transactivation.