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Molecular and Cellular Biology, January 2006, p. 50-62, Vol. 26, No. 1
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.1.50-62.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Transactivation of Platelet-Derived Growth Factor Receptor {alpha} by the GTPase-Deficient Activated Mutant of G{alpha}12

Rashmi N. Kumar, Ji Hee Ha, Rangasudhagar Radhakrishnan, and Danny N. Dhanasekaran*

Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140

Received 12 September 2005/ Accepted 12 October 2005

The GTPase-deficient, activated mutant of G{alpha}12 (G{alpha}12Q229L, or G{alpha}12QL) induces neoplastic growth and oncogenic transformation of NIH 3T3 cells. Using microarray analysis, we have previously identified a role for platelet-derived growth factor receptor {alpha} (PDGFR{alpha}) in G{alpha}12-mediated cell growth (R. N. Kumar et al., Cell Biochem. Biophys. 41:63-73, 2004). In the present study, we report that G{alpha}12QL stimulates the functional expression of PDGFR{alpha} and demonstrate that the expression of PDGFR{alpha} by G{alpha}12QL is dependent on the small GTPase Rho. Our results indicate that it is cell type independent as the transient expression of G{alpha}12QL or the activation of G{alpha}12-coupled receptors stimulates the expression of PDGFR{alpha} in NIH 3T3 as well as in human astrocytoma 1321N1 cells. Furthermore, we demonstrate the presence of an autocrine loop involving PDGF-A and PDGFR{alpha} in G{alpha}12QL-transformed cells. Analysis of the functional consequences of the G{alpha}12-PDGFR{alpha} signaling axis indicates that G{alpha}12 stimulates the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway through PDGFR. In addition, we show that G{alpha}12QL stimulates the phosphorylation of forkhead transcription factor FKHRL1 via AKT in a PDGFR{alpha}- and PI3K-dependent manner. Since AKT promotes cell growth by blocking the transcription of antiproliferative genes through the inhibitory phosphorylation of forkhead transcription factors, our results describe for the first time a PDGFR{alpha}-dependent signaling pathway involving PI3K-AKT-FKHRL1, regulated by G{alpha}12QL in promoting cell growth. Consistent with this view, we demonstrate that the expression of a dominant negative mutant of PDGFR{alpha} attenuated G{alpha}12-mediated neoplastic transformation of NIH 3T3 cells.

* Corresponding author. Mailing address: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N. Broad Street, 556 AHB, Philadelphia, PA 19140. Phone: (215) 707-1941. Fax: (215) 707-5963. E-mail: danny001{at}temple.edu.

Molecular and Cellular Biology, January 2006, p. 50-62, Vol. 26, No. 1
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.1.50-62.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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