HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Taylor, C. C. Search for Related Content PubMed PubMed Citation Articles by Taylor, C. C. Agricola Articles by Taylor, C. C.

Src Tyrosine Kinase-Induced Loss of Luteinizing Hormone Responsiveness Is via a Ras-Dependent, Phosphatidylinositol-3-Kinase Independent Pathway¹

^a Department of Cell Biology, Georgetown University School of Medicine, Washington, District of Columbia 20007

Gonadotropins stimulate gonadal cell steroid secretion primarily through activation of a cAMP-protein kinase A signal transduction pathway. Various growth factors have been shown to inhibit gonadotropin-stimulated steroidogenesis, however, the intracellular signaling cascades involved in growth factor inhibition have not been characterized. The present study investigated whether Src tyrosine kinase, a nonreceptor tyrosine kinase activated in response to growth factor stimulation and previously shown to inhibit LH-stimulated progesterone secretion, acts via activation of Ras stimulated pathways, phosphatidylinositol-3-kinase (PI3-kinase) stimulated pathways, or both in MA10 Leydig cells. Direct activation of Src in MA10 cells that express a temperature sensitive Src was associated with an increase in GTP-bound Ras, indicating increased Ras activity in response to Src activation. Direct activation of Ras by way of expression of a constitutively active Ras (Ras+) was associated with a decrease in LH responsiveness. Coexpression of a dominant negative Src, which by itself increases LH responsiveness in MA10 cells, had no effect on Ras+ inhibition on LH responsiveness, further demonstrating that Src is upstream of Ras. In addition, MA10^Ras+ cells were relatively unresponsive to cholera toxin or 8-bromo cAMP, indicating the effects of Ras are independent of cAMP generation. Wortmannin, a PI3-kinase inhibitor, did not restore LH responsiveness to cells expressing activated Src or constitutively active Ras. These results demonstrate that Src activates a Ras pathway in MA10 Leydig cells, and that activation of Ras is associated with a loss of LH responsiveness that is independent of PI3-kinase.

First decision: 16 November 2001.

¹ Supported by grant HD-36013 from the National Institutes of Health.

² Correspondence: Chris Taylor, Department of Cell Biology, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, DC 20007. FAX: 202 687 1823; cct5{at}georgetown.edu

This article has been cited by other articles:

				T. Mizutani, K. Shiraishi, T. Welsh, and M. Ascoli Activation of the Lutropin/Choriogonadotropin Receptor in MA-10 Cells Leads to the Tyrosine Phosphorylation of the Focal Adhesion Kinase by a Pathway that Involves Src Family Kinases Mol. Endocrinol., March 1, 2006; 20(3): 619 - 630. [Abstract] [Full Text] [PDF]

				W. Li, H. Amri, H. Huang, C. Wu, and V. Papadopoulos Gene and Protein Profiling of the Response of MA-10 Leydig Tumor Cells to Human Chorionic Gonadotropin J Androl, November 1, 2004; 25(6): 900 - 913. [Abstract] [Full Text] [PDF]