c-Src Signaling Induced by the Adapters Sin and Cas Is Mediated by Rap1 GTPase

Abstract

Oncogenic Src proteins have been extensively studied to gain insight into the signaling mechanisms of Src. To better understand signaling through wild-type Src, we used an approach that involves activation of Src signaling through the binding of physiologic ligands to the Src SH3 domain. To this end, we used full-length and truncated versions of the multiadapter molecules Cas and Sin to activate c-Src, and we examined the intracellular pathways that mediate Src signaling under these conditions. We show that although all proteins bind to and are phosphorylated by c-Src, quantitative differences exist in the ability of the different ligands to activate c-Src signaling. In addition, we show that Sin-and Cas-induced Src signaling, as assayed by transcriptional activation, is exclusively mediated through a pathway that involves the adapter Crk and the GTP-binding protein Rap1. These data are in contrast to previous observations showing Ras to mediate signaling downstream of transforming Src alleles. In our system, we found that signaling through the oncogenic SrcY527 mutant is indeed mediated by Ras. In addition, we found that Rap1 also mediates oncogenic Src signaling. Our results show for the first time that Rap1 mediates c-Src kinase signaling and reveal mechanistic differences in the signaling properties of wild-type and transforming Src proteins.

Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor

“…Such a mechanism, in which the substrate plays an active role in inducing its own phosphorylation by an otherwise inactive kinase, has obvious advantages where indiscriminate kinase activity can lead to disregulated signaling. A similar mechanism may be involved in phosphorylation by the Src kinase of p130 Cas and the Cas-like protein Sin, which can engage both the SH3 and SH2 domains of Src (Alexandropoulos and Baltimore, 1996;Burnham et al, 2000;Xing et al, 2000).…”

G protein coupled receptor signaling through the Src and Stat3 pathway: role in proliferation and transformation

“…The di erent small G proteins may Xing et al, 2000). The role of Ras signaling in Stat3 activation has been demonstrated for a number of years, whereby Ras activation of MAPK 1, 2 and the subsequent MAPK 1, 2 phosphorylation of Stat3 may be required for Stat3 activity (Herrmann et al, 1996).…”

The intrinsic ability of AFAP-110 to alter actin filament integrity is linked with its ability to also activate cellular tyrosine kinases

“…These activation events normally occur in response to cellular signals, e.g., growth factors interacting with their receptors (Brown and Cooper, 1996). These pathways are thought to proceed through Src, with the subsequent phosphorylation of substrates and activation of downstream signaling members, including Ras (He et al, 2000), pp125 FAK (Thomas et al, 1998), Crk (Sabe et al, 1992) and pp130 Cas (Xing et al, 2000).…”