Cbl Associates with Pyk2 and Src to Regulate Src Kinase Activity, αvβ3 Integrin-Mediated Signaling, Cell Adhesion, and Osteoclast Motility
A Sanjay, A Houghton, L Neff, E DiDomenico… - The Journal of cell …, 2001 - rupress.org
A Sanjay, A Houghton, L Neff, E DiDomenico, C Bardelay, E Antoine, J Levy, J Gailit…
The Journal of cell biology, 2001•rupress.orgThe 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 αvβ3 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 …
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 αvβ3 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 …
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 αvβ3 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 αvβ3 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.
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