CK1α protects WAVE from degradation to regulate cell shape and motility in the immune response
Autor: | Marianne van Cann, Sven Bogdan, Alexander Hirschhäuser |
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Rok vydání: | 2021 |
Předmět: |
CK2
Motility RAC1 macromolecular substances Cell motility Biology Microtubule Dynamics Ubiquitin-dependent protein degradation Collective Cell Migration Humans Cell migration Phosphorylation Actin CK1α Ubiquitin Kinase Macrophages Immunity Casein Kinase Ialpha Cell Biology Lamellipodia Wiskott-Aldrich Syndrome Protein Family Ubiquitin ligase Cell biology Proteasome biology.protein Cell shape WAVE Drosophila Lamellipodium Arp2/3 Research Article |
Zdroj: | Journal of Cell Science article-version (VoR) Version of Record |
ISSN: | 1477-9137 0021-9533 |
Popis: | 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 (CK1α) as a regulator of WAVE, thereby controlling cell shape and cell motility in Drosophila macrophages. CK1α binds and phosphorylates WAVE in vitro. Phosphorylation of WAVE by CK1α appears not to be required for activation but, rather, regulates its stability. Pharmacologic inhibition of CK1α promotes ubiquitin-dependent degradation of WAVE. Consistently, loss of Ck1α but not ck2 function phenocopies the depletion of WAVE. Phosphorylation-deficient mutations in the CK1α 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 CK1α-depleted macrophages. Therefore, we conclude that basal phosphorylation of WAVE by CK1α 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. Summary: We identified CK1α as a novel regulator of WAVE controlling cell shape and motility in immune response. Basal phosphorylation of WAVE by CK1α protects it from premature proteasomal degradation. |
Databáze: | OpenAIRE |
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