In the ERK-Src "switch" model, cortactin tyrosine phosphorylation by Src serves to downregulate N-WASp activity promoted by S405/418 phosphorylation [15].
Competitive binding of other proteins containing proline-rich domains and phospho-tyrosine containing motifs to respectively the SH3 and SH2 domains of c-Src allows a switch to an opened conformation.
These data support the idea that Src operates as a "switch" in concert with PI3K for activation of Akt in response to ghrelin.
As Dab1 acts as a Src family kinase (SFK) switch, the lack of Dab1 prevents Reelin-induced SFK activation.
Additionally Zhang et al. [ 28] indicated a biphasic effect of EGF on breast cancer cell proliferation and demonstrated that Src functions as a switch of EGF signaling, depending on EGF concentration.
Thus c-Src functions as a switch that initiates the Akt pathway associated to both the Gi/o-protein dependent pathway and β-arrestin-scaffolded complex.
However as both vinexin and utrophin bind the same region when not phosphorylated, there could be direct competition between the two proteins for the SH3 motif to which vinexin binds and the overlapping type 1 WW domain motif to which utrophin binds (dystrophin is not present in myoblasts; see Figure 2C), rather than Src modulated phosphorylation-dependent switching for this site.
Activation thus entails a shuffling of salt-bridge and polar hydrogen-bond partners, described in the case of Src kinases as an 'electrostatic switch' (Ozkirimli and Post, 2006; Banavali and Roux, 2009).
In previous work, we described that the cortactin SH3 domain is able to activate N-WASP and we proposed a model for the regulation of N-WASP activation by cortactin, in which cortactin is switched on by Erk phosphorylation of serines 405 and 418, while it is switched off by Src phosphorylation of tyrosines 421, 466 and 482 [ 14].
In podosomes however, there does appear to be Src-mediated Y890 phosphorylation-dependent switch [ 47].
Site-specific cleavage of hnRNP K represents a second molecular switch besides c-Src dependent Y458 phosphorylation, which modulates mRNA interaction specifically.
