Wnt3a stimulates Src docking to, activation by, and phosphorylation of Dvl2. In this working model, at resting state (in the absence of Wnt stimulation), Src family TKs are in an autoinhibitory `inactive' confirmation. For Src family kinases, two intramolecular interactions tightly regulate enzymatic activity: an interaction between the SH2 domain and the C-terminal tail and an interaction between the SH3 domain and a polyproline type II helix in the SH2-kinase linker region. Wnt3a stimulation of Frizzled-1 and LRP5/6 activates the `canonical' pathway in which multi-protein complexes that include Dvl2 docking via PDZ ligand and PDZ-binding domains. Our results indicate that the SH3 domain of Src family kinase binds to Dvl2 SH3-binding domain (residues 370-376) as well as to a larger, proline-rich C-terminal domain (511-736; proline-rich binding domain, PRO-RD) of Dvl2, or both. Through docking to Dvl2, autoinhibitory conformation of Src is released, disrupted by the SH3 domain and a polyproline type II helix in the SH2-kinase linker region. Wnt3a not only induces the docking of Src to Dvl2, but also release of Src from autoinhibition (i.e. activation), as well as Src-catalyzed phosphorylation of Src substrates (including Dvl2 in the DIX, PDZ and DEP domains) found in the Dvl2-based multiprotein complexes. Thus, Src is a positive regulator of Wnt canonical signaling, which acts by docking to and being activated by Dvl2 in response to Wnt stimulation. Red circles represent tyrosine phosphorylation sites. The schematic of the multiprotein complexes has been simplified. Axin, GSK3β, APC and many other components of the multiprotein complexes are not identified individually in this schematic.
