TY - JOUR
T1 - Identification of a novel integrin signaling pathway involving the kinase Syk and the guanine nucleotide exchange factor Vav1
AU - Miranti, Cindy K.
AU - Leng, Lijun
AU - Maschberger, Petra
AU - Brugge, Joan S.
AU - Shattil, Sanford J.
N1 - Funding Information:
The authors are grateful to A. Altman, M. Renshaw, M. Schwartz, M. Simon, S. Burakoff, M. Weber, and P. Tsichlis for generous gifts of plasmid reagents. We are also thankful to M. Ginsberg for the A5 CHO cell line, and K. Zoller and I. MacNeil for the Syk antibody and the Myc–Syk and Myc–Syk K402R expression plasmids. These studies were supported in part by grants from the National Institutes of Health (HL56595, HL57900 to S.J.S.), (CA27951, CA78773 to J.S.B.) and (CA72203 to C.K.M.).
PY - 1998/12/3
Y1 - 1998/12/3
N2 - Background: Integrins induce the formation of large complexes of cytoskeletal and signaling proteins, which regulate many intracellular processes. The activation and assembly of signaling complexes involving focal adhesion kinase (FAK) occurs late in integrin signaling, downstream from actin polymerization. Our previous studies indicated that integrin-mediated activation of 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 αIIbβ3. The guanine nucleotide exchange factor Vav1 was inducibly phosphorylated in a Sykdependent manner in cells following their attachment to fibrinogen. Together, Syk and Vav1 triggered lamellipodia formation in fibrinogen-adherent cells and both Syk and Vav1 colocalized with αIIbβ3 in lamellipodia but not in focal adhesions. Additionally, Syk and Vav1 cooperatively induced activation of Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase 2 (ERK2) and the kinase Akt, and phosphorylation of the oncoprotein Cbl in fibrinogen-adherent cells. Activation of all of these proteins 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 actin polymerization. This pathway may regulate multiple downstream events in hematopoietic cells, including Rac-induced lamellipodia formation, tyrosine phosphorylation of Cbl, and activation of JNK, ERK2 and the phosphatidylinositol 3'-kinase-regulated kinase Akt.
AB - Background: Integrins induce the formation of large complexes of cytoskeletal and signaling proteins, which regulate many intracellular processes. The activation and assembly of signaling complexes involving focal adhesion kinase (FAK) occurs late in integrin signaling, downstream from actin polymerization. Our previous studies indicated that integrin-mediated activation of 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 αIIbβ3. The guanine nucleotide exchange factor Vav1 was inducibly phosphorylated in a Sykdependent manner in cells following their attachment to fibrinogen. Together, Syk and Vav1 triggered lamellipodia formation in fibrinogen-adherent cells and both Syk and Vav1 colocalized with αIIbβ3 in lamellipodia but not in focal adhesions. Additionally, Syk and Vav1 cooperatively induced activation of Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase 2 (ERK2) and the kinase Akt, and phosphorylation of the oncoprotein Cbl in fibrinogen-adherent cells. Activation of all of these proteins 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 actin polymerization. This pathway may regulate multiple downstream events in hematopoietic cells, including Rac-induced lamellipodia formation, tyrosine phosphorylation of Cbl, and activation of JNK, ERK2 and the phosphatidylinositol 3'-kinase-regulated kinase Akt.
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U2 - 10.1016/S0960-9822(07)00559-3
DO - 10.1016/S0960-9822(07)00559-3
M3 - Article
C2 - 9843681
AN - SCOPUS:0032481142
SN - 0960-9822
VL - 8
SP - 1289
EP - 1299
JO - Current Biology
JF - Current Biology
IS - 24
ER -