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Published online 8 January 2001. doi:10.1083/jcb.152.1.181
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© The Rockefeller University Press, 0021-9525/2001/1/181/ $5.00
The Journal of Cell Biology, Volume 152, Number 1, January 8, 2001 181-196

Original Article

Cbl Associates with Pyk2 and Src to Regulate Src Kinase Activity, {alpha}vß3 Integrin-mediated Signaling, Cell Adhesion, and Osteoclast Motility

Archana Sanjaya, Adam Houghtona, Lynn Neffa, Emilia DiDomenicoa, Chantal Bardelayb, Evelyne Antoineb, Joan Levya, James Gailitc, David Bowtelld, William C. Hornea, and Roland Barona
a Department of Cell Biology and Orthopedics, Yale University School of Medicine, New Haven, Connecticut 06510
b Hoechst Marion Roussel, Bone Disease Group, Romainville, 93235 France
c Jules Wellton Rheingold Texas Research Foundation, State University of New York, Stony Brook, New York 11790
d Peter MacCallum Cancer Institute, East Melborne Victoria, 3002 Australia

Correspondence to: Roland Baron, Department of Cell Biology and Orthopedics, Yale University School of Medicine, P.O. Box 208044, New Haven, CT 06510. Tel:203-785-5986 Fax:203-785-2744 E-mail:roland.baron{at}yale.edu.

The signaling events downstream of integrins that regulate cell attachment and motility are only partially understood. Using osteoclasts and transfected 293 cells, we find that a molecular complex comprising Src, Pyk2, and Cbl functions to regulate cell adhesion and motility. The activation of integrin {alpha}vß3 induces the [Ca2+]i-dependent phosphorylation of Pyk2 Y402, its association with Src SH2, Src activation, and the Src SH3-dependent recruitment and phosphorylation of c-Cbl. Furthermore, the PTB domain of Cbl is shown to bind to phosphorylated Tyr-416 in the activation loop of Src, the autophosphorylation site of Src, inhibiting Src kinase activity and integrin-mediated adhesion. Finally, we show that deletion of c Src or c-Cbl leads to a decrease in osteoclast migration. Thus, binding of {alpha}vß3 integrin induces the formation of a Pyk2/Src/Cbl complex in which Cbl is a key regulator of Src kinase activity and of cell adhesion and migration. These findings may explain the osteopetrotic phenotype in the Src-/- mice.

Key Words: Cbl, Src, Pyk2, osteoclast, vitronectin receptor ({alpha}vß3)


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