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Originally published In Press as doi:10.1074/jbc.M109068200 on December 20, 2001

J. Biol. Chem., Vol. 277, Issue 10, 7875-7881, March 8, 2002
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Vascular Endothelial Growth Factor-induced Migration of Multiple Myeloma Cells Is Associated with beta 1 Integrin- and Phosphatidylinositol 3-Kinase-dependent PKCalpha Activation*

Klaus Podar, Yu-Tzu Tai, Boris K. Lin, Radha P. Narsimhan, Martin Sattler, Takashi Kijima, Ravi Salgia, Deepak Gupta, Dharminder Chauhan, and Kenneth C. AndersonDagger

From the Jerome Lipper Multiple Myeloma Research Center/Dana-Farber Cancer Institute and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

In multiple myeloma (MM), migration is necessary for the homing of tumor cells to bone marrow (BM), for expansion within the BM microenvironment, and for egress into the peripheral blood. In the present study we characterize the role of vascular endothelial growth factor (VEGF) and beta 1 integrin (CD29) in MM cell migration. We show that protein kinase C (PKC) alpha  is translocated to the plasma membrane and activated by adhesion of MM cells to fibronectin and VEGF. We identify beta 1 integrin modulating VEGF-triggered MM cell migration on fibronectin. We show that transient enhancement of MM cell adhesion to fibronectin triggered by VEGF is dependent on the activity of both PKC and beta 1 integrin. Moreover, we demonstrate that PKCalpha is constitutively associated with beta 1 integrin. These data are consistent with PKCalpha -dependent exocytosis of activated beta 1 integrin to the plasma membrane, where its increased surface expression mediates binding to fibronectin; conversely, catalytically active PKCalpha -driven internalization of beta 1 integrin results in MM cell de-adhesion. We show that the regulatory subunit of phosphatidylinositol (PI) 3-kinase (p85) is constitutively associated with FMS-like tyrosine kinase-1 (Flt-1). VEGF stimulates activation of PI 3-kinase, and both MM cell adhesion and migration are PI 3-kinase-dependent. Moreover, both VEGF-induced PI 3-kinase activation and beta 1 integrin-mediated binding to fibronectin are required for the recruitment and activation of PKCalpha . Time-lapse phase contrast video microscopy (TLVM) studies confirm the importance of these signaling components in VEGF-triggered MM cell migration on fibronectin.

* This work was supported by an International Myeloma Foundation/ Brian D. Novis/Benson Klein Research grant award (to K. P.), National Institutes of Health Grant PO-1 78378, and the 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. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dana-Farber Cancer Inst., 44 Binney St., Boston, MA 02115. Tel.: 617-632-2144; Fax: 617-632-2140; E-mail: kenneth_anderson@dfci.harvard.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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