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J. Biol. Chem., Vol. 278, Issue 40, 38628-38636, October 3, 2003

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The Inositol 5'-Phosphatase SHIP-1 and the Src Kinase Lyn Negatively Regulate Macrophage Colony-stimulating Factor-induced Akt Activity^*

Christopher P. Baran  , Susheela Tridandapani   ¶, Cheryl D. Helgason ||, R. Keith Humphries ||, Gerald Krystal || and Clay B. Marsh   **

From the Dorothy M. Davis Heart and Lung Research Institute and the Department of Internal Medicine, Ohio State University, Columbus, Ohio 43210 and the ^||Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada

Upon encountering macrophage colony-stimulating factor (M-CSF), human monocytes undergo a series of cellular signaling events leading to an increase in Akt activity. However, the regulation of these events is not completely understood. Because the inositol 5'-phosphatase SHIP-1 is an important regulator of intracellular levels of phosphatidylinositol 3,4,5-trisphosphate, an important second messenger necessary for Akt activation, we hypothesized that SHIP-1 was involved in the regulation of M-CSF receptor (M-CSF-R)-induced Akt activation. In the human monocytic cell line, THP-1, SHIP-1 became tyrosine-phosphorylated following M-CSF activation in a Src family kinase-dependent manner. Transfection of 3T3-Fms cells, which express the human M-CSF-R, with wild-type SHIP-1 showed that SHIP-1 was necessary for the negative regulation of M-CSF-induced Akt activation. In THP-1 cells, SHIP-1 bound Lyn, independent of the kinase activity of Lyn, following M-CSF activation. Utilizing a glutathione S-transferase fusion protein, we found that SHIP-1 bound to Lyn via the SHIP-1 Src homology 2 domain. Furthermore, transfection of THP-1 cells with a wild-type SHIP-1 construct reduced NF-B-dependent transcriptional activation of a reporter gene, whereas a SHIP-1 Src homology 2 domain construct resulted in an increase in NF-B activation. Additionally, in 3T3-Fms cells, Lyn enhanced the ability of SHIP-1 to regulate Akt activation by stabilizing SHIP-1 at the cellular membrane. Finally, macrophages isolated from both SHIP-1- and Lyn-deficient mice exhibited enhanced Akt phosphorylation following M-CSF stimulation. These data provide the first evidence of the involvement of both SHIP-1 and Lyn in the negative regulation of M-CSF-R-induced Akt activation.

Received for publication, May 13, 2003 , and in revised form, July 24, 2003.

^* This work was supported in part by National Institutes of Health Grants RO1HL63800, RO1HL66108, RO1HL67176, and PO1HL70294; an American Lung Association Johnie Walker Murphy Career Investigator award; and the Kelly Clark Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Fellow of the Leukemia and Lymphoma Society.

^** To whom correspondence should be addressed: Rm. 201, Dorothy M. Davis Heart and Lung Research Inst., 473 W. 12th Ave., Columbus, OH 43210. Tel.: 614-293-4925; Fax: 614-688-4662; E-mail: marsh.2{at}osu.edu.

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