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Phosphorylation of CYFIP2, a component of the WAVE-regulatory complex, regulates dendritic spine density and neurite outgrowth in cultured hippocampal neurons potentially by affecting the complex assembly

Authors
Lee, YeunkumKim, DoyounRyu, Jae RyunZhang, YinhuaKim, ShinhyunKim, YoonheeLee, BokyoungSun, WoongHan, Kihoon
Issue Date
16-8월-2017
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Keywords
CYFIP1; 2; dendritic spine; Nap1; neurite outgrowth; phosphorylation; WAVE-regulatory complex
Citation
NEUROREPORT, v.28, no.12, pp.749 - 754
Indexed
SCIE
SCOPUS
Journal Title
NEUROREPORT
Volume
28
Number
12
Start Page
749
End Page
754
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/82546
DOI
10.1097/WNR.0000000000000838
ISSN
0959-4965
Abstract
Actin dynamics is a critical mechanism underlying many cellular processes in neurons. The heteropentameric WAVE-regulatory complex (WRC), consisting of WAVE, CYFIP1/2, Nap, Abi, and HSPC300, is a key regulator of actin dynamics that activates the Arp2/3 complex to initiate actin polymerization and branching. The WRC is basally inactive because of intermolecular interactions among the components, which can be modulated by bindings of phospholipids and Rac1, and phosphorylations of WAVE and Abi. However, the phosphorylation of other components of WRC and their functional significance remain largely unknown. To address this issue, we focused on CYFIP1/2, in which we found two brain-specific phosphorylation sites (S582 of CYFIP2 and T1068/T1067 of CYFIP1/2) from a publicly available phosphoproteome database. To understand their functional effects, we overexpressed wild-type, phospho-blocking, or phospho-mimetic mutants of CYFIP2 in cultured hippocampal neurons, and found that only T1067A CYFIP2 decreased the density of stubby spines. Moreover, overexpression of wild-type CYFIP2 increased neurite length, but T1067A did not exert this effect. To understand the mechanism, we modeled CYFIP2 phosphorylation in the crystal structure of WRC and found that T1067 phosphorylation could weaken the interaction between CYFIP2 and Nap1 by inducing conformational changes of CYFIP2 -helical bundles. In the co-immunoprecipitation assay, however, wild-type, T1067A, and T1067E CYFIP2 showed similar interaction levels to Nap1, suggesting that T1067 phosphorylation alone is not sufficient to disrupt the interaction. Considering that the activation of WRC requires disassembly of the complex, our results suggest that T1067 phosphorylation, together with other factors, could contribute toward the activation process.
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