CK1α protects WAVE from degradation to regulate cell shape and motility in the immune response

The WAVE regulatory complex (WRC) is the main activator of the Arp2/3 complex, promoting lamellipodial protrusions in migrating cells. The WRC is basally inactive but can be activated by Rac1 and phospholipids, and through phosphorylation. However, the in vivo relevance of the phosphorylation of WAVE proteins remains largely unknown. Here, we identified casein kinase I alpha (CK1 alpha) as a regulator of WAVE, thereby controlling cell shape and cell motility in Drosophila macrophages. CK1 alpha binds and phosphorylates WAVE in vitro. Phosphorylation ofWAVE by CK1 alpha appears not to be required for activation but, rather, regulates its stability. Pharmacologic inhibition of CK1 alpha promotes ubiquitin-dependent degradation of WAVE. Consistently, loss of Ck1 alpha but not ck2 function phenocopies the depletion of WAVE. Phosphorylation-deficient mutations in the CK1 alpha consensus sequences within the VCA domain of WAVE can neither rescue mutant lethality nor lamellipodium defects. By contrast, phosphomimetic mutations rescue all cellular and developmental defects. Finally, RNAi-mediated suppression of 26S proteasome or E3 ligase complexes substantially rescues lamellipodia defects in CK1 alpha-depleted macrophages. Therefore, we conclude that basal phosphorylation of WAVE by CK1 alpha protects it from premature ubiquitin-dependent degradation, thus promoting WAVE function in vivo. This article has an associated First Person interview with the first author of the paper.

Automated summary

CK1 alpha regulates the stability of WAVE by phosphorylating it, protecting it from premature degradation and promoting its function in vivo. Loss of CK1 alpha function phenocopies depletion of WAVE, indicating the importance of CK1 alpha in regulating cell motility. Pharmacologic inhibition of CK1 alpha leads to ubiquitin-dependent degradation of WAVE.