34 research outputs found
Integrin-mediated signal transduction pathways
Integrins serve as adhesion receptors for
extracellular matrix proteins and also transduce
biochemical signals into the cell. They regulate a variety
of cellular functions, including spreading, migration,
proliferation and apoptosis. Many signaling pathways
downstream of integrins have been identified and
characterized and are discussed here. In particular,
integrins regulate many protein tyrosine kinases and
phosphatases, such as FAK and Src, to coordinate many
of the cell processes mentioned above. The regulation of
MAP kinases by integrins is important for cell growth or
other functions, and the putative roles of Ras and FAK in
these pathways are discussed. Phosphatidylinositol lipids
and their modifying enzymes, particularly PI 3-kinase,
are strongly implicated as mediators of integrinregulated
cytoskeletal changes and cell migration.
Similarly, actin cytoskeleton regulation by the Rho
family of GTPases is coordinated with integrin signaling
to regulate cell spreading and migration, although the
exact relationship between these pathways is not clear.
Finally, intracellular pH and calcium fluxes by integrins
are suggested to affect a variety of cellular proteins and
functions
Interactions of Human Embryonic Stem Cell-Derived Neural Progenitors with an Electrospun Nanofibrillar Surface in Vitro
Fibronectin Promotes Tyrosine Phosphorylation of Paxillin and Cell Invasiveness in the Gastric Cancer Cell Line AGS
Requirement of phosphatidylinositol 3-kinase in focal adhesion kinase-promoted cell migration
We have previously shown that overexpression of focal adhesion kinase (FAK) in Chinese hamster ovary (CHO) cells promoted their migration on fibronectin, This effect was dependent on the phosphorylation of FAK at Tyr-397, This residue was known to serve as a binding site for both Src and phosphatidylinositol 3-kinase (PI3K), implying that either one or both are required for FAR to promote cell migration. In this study, we have examined the role of PI3K in FAR-promoted cell migration. We have demonstrated that the PI3K inhibitors, wortmannin and LY294002, were able to inhibit FAR-promoted migration in a dose-dependent manner. Furthermore, a FAK mutant capable of binding Src but not PI3K was generated by a substitution of Asp residue 395 with Ala. When overexpressed in CHO cells, this differential binding mutant failed to promote cell migration although its association with Src was retained. Together, these results strongly suggest that PI3K binding is required for FAK to promote cell migration and that the binding of Src and p130(Cas) to FAK may not be sufficient for this event
Src phosphorylates Grb2-associated binder 1 upon hepatocyte growth factor stimulation
Grb2-associated binder 1 (Gab1) is known to play an important role in hepatocyte growth factor (HGF) signaling, which rapidly becomes tyrosine-phosphorylated upon HGF stimulation. In this study, we found that the tyrosine phosphorylation of Gab1 in the cells derived from Src/Yes/Fyn null mouse embryos was similar to40% lower than that in their wild type counterparts upon HGF stimulation. Increased expression of wild-type Src enhanced HGF-induced phosphorylation of Gab1, and, in contrast, expression of the Src kinase-deficient mutant or treatment of the specific Src inhibitor PP1 suppressed it. Expression of a constitutively active Src mutant (Y527F) or oncogenic v-Src led to a prominent increase in Gab1 phosphorylation independent of HGF stimulation. Moreover, Src interacted with Gab1 via both its Src homology 2 and 3 domains and was capable of phosphorylating purified Gab1 in vitro. Finally, the increased phosphorylation of Gab1 by Src selectively potentiated HGF-induced activation of ERK and AKT. Taken together, our results establish a new role for Src in HGF-induced Gab1 phosphorylation