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J. Biol. Chem., Vol. 279, Issue 20, 21658-21665, May 14, 2004

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Critical Role for Hematopoietic Cell Kinase (Hck)-mediated Phosphorylation of Gab1 and Gab2 Docking Proteins in Interleukin 6-induced Proliferation and Survival of Multiple Myeloma Cells^*

Klaus Podar, Gustavo Mostoslavsky¶, Martin Sattler¶, Yu-Tzu Tai, Toshiaki Hayashi, Laurence P. Catley, Teru Hideshima, Richard C. Mulligan, Dharminder Chauhan, and Kenneth C. Anderson||

From the Department of Medical Oncology, Dana-Farber Cancer Institute, and the Department of Genetics, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Interleukin-6 (LI-6) is a known growth and survival factor in multiple myeloma via activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling cascade. In this report we show that Grb2-associated binder (Gab) family adapter proteins Gab1 and Gab2 are expressed by multiple myeloma cells; and that interleukin-6 induces their tyrosine phosphorylation and association with downstream signaling molecules. We further demonstrate that these events are Src family tyrosine kinase-dependent and specifically identify the role of hematopoietic cell kinase (Hck) as a new Gab family adapter protein kinase. Conversely, inhibition of Src family tyrosine kinases by the pyrazolopyrimidine PP2, as in kinase-inactive Hck mutants, significantly reduces IL-6-triggered activation of extracellular signal-regulated kinase and AKT-1, leading to significant reduction of multiple myeloma cell proliferation and survival. Taken together, these results delineate a key role for Hck-mediated phosphorylation of Gab1 and Gab2 docking proteins in IL-6-induced proliferation and survival of multiple myeloma cells and identify tyrosine kinases and downstream adapter proteins as potential new therapeutic targets in multiple myeloma.

Received for publication, June 2, 2003 , and in revised form, February 27, 2004.

^* This work was supported by a Multiple Myeloma Research Foundation Senior Research Grant Award (to K. P.), National Institutes of Health Grant PO-1 78378, and a Doris Duke Distinguished Clinical Research Scientist award (to K. C. A.). 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.

^¶ Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Dept. of Medical Oncology, Dana-Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, 44 Binney St., Boston, MA 02115. Tel.: 617-632-2144; Fax: 617-632-2140; E-mail: Kenneth_Anderson{at}dfci.harvard.edu.

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