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 Nielsen-Preiss, S. M. Articles by Wierman, M. E. Search for Related Content PubMed PubMed Citation Articles by Nielsen-Preiss, S. M. Articles by Wierman, M. E.

Adhesion-Related Kinase Induction of Migration Requires Phosphatidylinositol-3-Kinase and Ras Stimulation of Rac Activity in Immortalized Gonadotropin-Releasing Hormone Neuronal Cells

Departments of Medicine (S.M.N.-P., M.P.A., M.X., J.E.P., M.E.W.), Physiology and Biophysics (M.E.W.), and Pharmacology (K.A.H.), The University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045; Research Service (S.M.N.-P., M.X., D.A.L., J.E.P., R.J.B., K.A.H., M.E.W.), Veterans Affairs Medical Center, Denver, Colorado 80220; and Amgen (B.C.V.), Thousand Oaks, California 91320

Address all correspondence and requests for reprints to: Margaret E. Wierman, Veterans Affairs Medical Center, 1055 Clermont Street, Box 111H, Denver, Colorado 80220. E-mail: Margaret.Wierman{at}UCHSC.edu.

GnRH neurons migrate into the hypothalamus during development. Although migratory defects may result in disordered activation of the reproductive axis and lead to delayed or absent sexual maturation, specific factors regulating GnRH neuronal migration remain largely unknown. The receptor tyrosine kinase, adhesion-related kinase (Ark) (also known as Axl, UFO, and Tyro7), has been implicated in the migration of GnRH neuronal cells. Binding of its ligand, growth arrest-specific gene 6 (Gas6), promotes cytoskeletal remodeling and migration of NLT GnRH neuronal cells via Rac and p38 MAPK. Here, we examined the Axl effectors proximal to Rac in the signaling pathway. Gas6/Axl-induced lamellipodia formation and migration were blocked after phosphatidylinositol-3-kinase (PI3K) inhibition in GnRH neuronal cells. The p85 subunit of PI3K coimmunoprecipitated with Axl and was phosphorylated in a Gas6-sensitive manner. In addition, PI3K inhibition in GnRH neuronal cells diminished Gas6-induced Rac activation. Exogenous expression of a dominant-negative form of Ras also decreased GnRH neuronal lamellipodia formation, migration, and Rac activation. PI3K inhibition blocked Ras in addition to Rac activation and migration. In contrast, pharmacological blockade of the phospholipase C effectors, protein kinase C or calcium/calmodulin protein kinase II, had no effect on Gas6/Axl signaling to promote Rac activation or stimulate cytoskeletal reorganization and migration. Together, these data show that the PI3K-Ras pathway is a major mediator of Axl actions upstream of Rac to induce GnRH neuronal cell migration.

This article has been cited by other articles:

				V. Kolsch, P. G. Charest, and R. A. Firtel The regulation of cell motility and chemotaxis by phospholipid signaling J. Cell Sci., March 1, 2008; 121(5): 551 - 559. [Abstract] [Full Text] [PDF]