CaMKIIα phosphorylation of Shank3 modulates ABI1-Shank3 interaction

CaMKII Phosphorylation Regulates Synaptic Enrichment of Shank3

“…4 ). Notably, two previous studies found that disruption of Shank3 S685 phosphorylation specifically abolished Shank3-ABI1 binding, but did not alter GKAP, cortactin, L-type Ca 2+ channel Ca v 1.3, or Homer binding ( Wang et al, 2020 ; Perfitt et al, 2020a ). Along with these previous findings, our results ( Fig.…”

“…However, because S782 phosphorylation didn't affect binding to PDZ proteins, the increased Shank3 S782A and PSD-95 synaptic puncta size is unlikely to be related with GKAP binding (Fig. 4) (Wang et al, 2019;Perfitt et al, 2020a). Pharmacological activation of global CaMKII in cultured neurons did not change colocalization between endogenous Shank3 and PSD-95 ( Fig.…”

“…We cannot completely exclude the possibility of S782 phosphorylation by other synaptic kinases in neurons, but we compared basal HA-Shank3 phosphorylation to CaMKII activated HA-Shank3 phosphorylation in the mass results from cell lines. The only other study reporting a direct phosphorylation of Shank3 by CaMKII involved in vitro assays assessing phosphorylation of GST-Shank3 (572–691) fusion proteins showing that Shank3 S685 can be phosphorylated by CaMKII ( Perfitt et al, 2020a ). Because this study looked specifically at a particular region of Shank3, it was not clear whether CaMKII had other targets within Shank3.…”

“…This particular site coincides with an ASD-associated variant site, and the phosphorylation and rare variant are associated with the recruitment of Abelson interactor 1 (ABI1) to Shank3 protein. These studies demonstrated S685 is phosphorylated in a transgenic mouse model ( Wang et al, 2020 ), that CaMKII and PKA can phosphorylate Shank3 S685 in vitro ( Wang et al, 2020 ; Perfitt et al, 2020a ), and the phosphorylation is required for the ABI1 interaction with Shank3 ( Wang et al, 2020 ; Perfitt et al, 2020a ).…”

“…For instance, PSD-95, an excitatory synapse scaffolding protein, has multiple phosphorylation sites, which are targeted by several kinases, such as JNK1, CDK5, and GSK3β, to modulate its synaptic accumulation and promote receptor clustering ( Morabito et al, 2004 ; Kim et al, 2007 ; Nelson et al, 2013 ). More recently, the regulation of Shank3 by phosphorylation of one residue, serine 685 (S685) has been reported using a variety of techniques ( Wang et al, 2020 ; Perfitt et al, 2020a ). This particular site coincides with an ASD-associated variant site, and the phosphorylation and rare variant are associated with the recruitment of Abelson interactor 1 (ABI1) to Shank3 protein.…”