Identification of a novel integrin signaling pathway involving the kinase Syk and the guanine nucleotide exchange factor Vav1

Background: Integrins induce the formation of large complexes of cytoskelet al and signaling proteins, which regulate many intracellular processes. The activation and assembly of signaling complexes involving focal adhesion ki nase (FAK) occurs late in integrin signaling, downstream from actin polymer ization. Our previous studies indicated that integrin-mediated activation o f the nonreceptor tyrosine kinase Syk in hematopoietic cells is independent of FAK and actin polymerization, and suggested the existence of a distinct signaling pathway regulated by Syk Results: Multiple proteins were found to be activated by Syk, downstream of engagement of the platelet/megakaryocyte-specific integrin alpha IIb beta 3. The guanine nucleotide exchange factor Vav1 was inducibly phosphorylated in a Syk-dependent manner in cells following their attachment to fibrinoge n. Together, Syk and Vav1 triggered lamellipodia formation in fibrinogen-ad herent cells and both Syk and Vav1 colocalized with alpha IIb beta 3 in lam ellipodia but not in focal adhesions. Additionally, Syk and Vav1 cooperativ ely induced activation of Jun N-terminal kinase (JNK), extracellular-signal -regulated kinase 2 (ERK2) and the kinase Akt, and phosphorylation of the o ncoprotein Cbl in fibrinogen-adherent cells. Activation of all of these pro teins by Syk and Vav1 was not dependent on actin polymerization. Conclusions: Syk and Vav1 regulate a unique integrin signaling pathway that differs from the FAK pathway in its proximity to the integrin itself, its localization to lamellipodia, and its activation, which is independent of a ctin polymerization. This pathway may regulate multiple downstream events i n hematopoietic cells, including Rac-induced lamellipodia formation. tyrosi ne phosphorylation of Cbl, and activation of JNK, ERK2 and the phosphatidyl inositol 3'-kinase-regulated kinase Akt.