Abstract
Bmx/Etk, a member of the Tec/Btk family of nonreceptor kinases, has recently been shown to mediate cell motility in signaling pathways that become activated upon integrin-mediated cell adhesion (Chen, R., Kim, O., Li, M., Xiong, X., Guan, J. L., Kung, H. J., Chen, H., Shimizu, Y., and Qiu, Y. (2001) Nat Cell Biol. 3, 439-444). The molecular mechanisms of Bmx-induced cell motility have so far remained unknown. Previous studies by us and others have demonstrated that a complex formation between the docking protein p130Cas (Cas) and the adapter protein Crk is instrumental in connecting several stimuli to the regulation of actin cytoskeleton and cell motility. We demonstrate here that expression of Bmx leads to an interaction between Bmx and Cas at membrane ruffles, which are sites of active actin remodeling in motile cells. Expression of Bmx also enhances tyrosine phosphorylation of Cas and Cas.Crk complex formation, and coexpression of Bmx with Cas results in an enhanced membrane ruffling and haptotactic cell migration. Importantly, a mutant form of Bmx that fails to interact with Cas also fails to induce cell migration. Furthermore, expression of a dominant-negative form of Cas that is incapable of interacting with Crk inhibits Bmx-induced membrane ruffling and cell migration. These studies suggest that Bmx-Cas interaction, phosphorylation of Cas by Bmx, and subsequent Cas.Crk complex formation functionally couple Bmx to the regulation of actin cytoskeleton and cell motility.
Highlights
The docking protein Cas becomes tyrosine-phosphorylated in an adhesion-dependent manner on FN and other extracellular matrix components and is involved in maintaining the integrity of the actin cytoskeleton and regulating cell migration by recruiting the adapter protein Crk [22, 30, 31, 45,46,47,48]
Chen et al [37] recently established that Bmx is involved in signaling downstream of integrins, which are key receptors regulating actin cytoskeleton and cell motility. These authors further demonstrated a causal relationship between Bmx expression and cell motility by showing that antisense-induced reduction of Bmx protein expression is associated with a significant inhibition of motility of prostate and breast carcinoma cells
Chen et al [37] showed that the activation of Bmx by integrins is mediated by Focal adhesion kinase (FAK), a key mediator of integrin signaling events leading to modulation of cell motility, and that Bmx is essential for FAK-induced cell motility [37]
Summary
Previous studies by us and others have demonstrated that a complex formation between the docking protein p130Cas (Cas) and the adapter protein Crk is instrumental in connecting several stimuli to the regulation of actin cytoskeleton and cell motility. We demonstrate here that expression of Bmx leads to an interaction between Bmx and Cas at membrane ruffles, which are sites of active actin remodeling in motile cells. A mutant form of Bmx that fails domain-containing proteins including Src kinases. The binding of Src kinases to FAK leads to further phosphorylation of FAK and to phosphorylation and activation of a number of cytoskeleton-linked proteins, which transduce integrin-generated signals to downstream signaling pathways At the N terminus, a Src-binding (SB) domain toward the C These studies suggest that Bmx-Cas interaction, phos- terminus, and an interior substrate domain (SD) (see Fig. 3A)
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