This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vulin, A. I. Articles by Stanley, F. M. Search for Related Content PubMed PubMed Citation Articles by Vulin, A. I. Articles by Stanley, F. M.

Integrin Activates Receptor-Like Protein Tyrosine Phosphatase , Src, and Rho to Increase Prolactin Gene Expression through a Final Phosphatidylinositol 3-Kinase/Cytoskeletal Pathway that Is Additive with Insulin

Department of Pharmacology (A.I.V., K.K.J., F.M.S.) and Kaplan Cancer Center (F.M.S.), New York University School of Medicine, New York, New York 10016

Address all correspondence and requests for reprints to: Dr. Frederick M. Stanley, Department of Pharmacology, MSB407, New York University Medical Center, 550 First Avenue, New York, New York 10016. E-mail: stanlf01{at}med.nyu.edu.

We previously showed that receptor-like protein tyrosine phosphatase (RPTP)- inhibited insulin-increased prolactin gene transcription. Others suggested that RPTP was a key intermediary between integrins and activation of Src. We present evidence that inhibition of insulin-increased prolactin gene transcription was secondary to RPTP activation of Src, reflecting its role as mediator of integrin responses. Src kinase activity was increased in GH4 cells transiently or stably expressing RPTP and cells plated on the integrin-5ß1 ligand fibronectin. C-terminal Src kinase inactivated Src and blocked RPTP inhibition of insulin-increased prolactin gene transcription. Expression of dominant-negative Src also prevented the RPTP-mediated inhibition of insulin-increased prolactin gene expression. Low levels of a constitutively active Src mutant (SrcY/F) stimulated whereas higher expression levels of Src Y/F inhibited prolactin gene expression. Src-increased prolactin gene transcription was inhibited by expression of a blocking Rho-mutant (RhoN19), suggesting that Src acted through or required active Rho. Experiments with an activated Rho-mutant (RhoL63) demonstrated a biphasic activation/repression of prolactin gene transcription that was similar to the effect of Src. The effects of both Src and Rho were phosphatidylinositol 3-kinase dependent. Expression of SrcY/F or RhoL63 altered the actin cytoskeleton and morphology of GH4 cells. Taken together, these data suggest a physiological pathway from the cell matrix to increased prolactin gene transcription mediated by RPTP/Src/Rho/phosphatidylinositol 3-kinase and cytoskeletal change that is additive with effects of insulin. Over activation of this pathway, however, caused extreme alteration of the cytoskeleton that blocked activation of the prolactin gene.

This article has been cited by other articles:

				C. Mikelis, E. Sfaelou, M. Koutsioumpa, N. Kieffer, and E. Papadimitriou Integrin {alpha}{nu}{beta}3 is a pleiotrophin receptor required for pleiotrophin-induced endothelial cell migration through receptor protein tyrosine phosphatase {beta}/{zeta} FASEB J, May 1, 2009; 23(5): 1459 - 1469. [Abstract] [Full Text] [PDF]

				F. M. Stanley Insulin-Increased Prolactin Gene Expression Requires Actin Treadmilling: Potential Role for P21 Activated Kinase Endocrinology, December 1, 2007; 148(12): 5874 - 5883. [Abstract] [Full Text] [PDF]

				D. Schaafsma, K. D. McNeill, G. L. Stelmack, R. Gosens, H. A. Baarsma, B. G. J. Dekkers, E. Frohwerk, J.-M. Penninks, P. Sharma, K. M. Ens, et al. Insulin increases the expression of contractile phenotypic markers in airway smooth muscle Am J Physiol Cell Physiol, July 1, 2007; 293(1): C429 - C439. [Abstract] [Full Text] [PDF]