RRC ID 46750
Author Marubashi S, Ohbayashi N, Fukuda M.
Title A Varp-Binding Protein, RACK1, Regulates Dendrite Outgrowth through Stabilization of Varp Protein in Mouse Melanocytes.
Journal J Invest Dermatol
Abstract Varp (VPS9-ankyrin repeat protein) in melanocytes is thought to function as a key player in the pigmentation of mammals. Varp regulates two different melanocyte functions: (i) transport of melanogenic enzymes to melanosomes by functioning as a Rab32/38 effector and (ii) promotion of dendrite outgrowth by functioning as a Rab21-guanine nucleotide exchange factor. The Varp protein level has recently been shown to be negatively regulated by proteasomal degradation through interaction of the ankyrin repeat 2 (ANKR2) domain of Varp with Rab40C. However, the molecular mechanisms by which Varp escapes from Rab40C and retains its own expression level remain completely unknown. Here, we identified RACK1 (receptor of activated protein kinase C 1) as a Varp-ANKR2 binding partner and investigated its involvement in Varp stabilization in mouse melanocytes. The results showed that knockdown of endogenous RACK1 in melanocytes caused dramatic reduction of the Varp protein level and inhibition of dendrite outgrowth, and intriguingly, overexpression of RACK1 inhibited the interaction between Varp and Rab40C and counteracted the negative effect of Rab40C on dendrite outgrowth. These findings indicated that RACK1 competes with Rab40C for binding to the ANKR2 domain of Varp and regulates dendrite outgrowth through stabilization of Varp in mouse melanocytes.
Volume 136(8)
Pages 1672-1680
Published 2016-8-1
DOI 10.1016/j.jid.2016.03.034
PII S0022-202X(16)31026-0
PMID 27066885
MeSH Animals Ankyrins / metabolism COS Cells Chlorocebus aethiops Dendrites / metabolism* Gene Expression Profiling Gene Expression Regulation* Green Fluorescent Proteins / metabolism Guanine Nucleotide Exchange Factors / metabolism* Melanocytes / cytology Melanocytes / metabolism* Melanosomes / metabolism Membrane Glycoproteins / metabolism Mice Neuropeptides / metabolism* Proteasome Endopeptidase Complex / metabolism Protein Binding Protein Domains Receptors for Activated C Kinase Two-Hybrid System Techniques
IF 7.143
Times Cited 8
DNA material pEF-FLAG-Varp (RDB14333) pEF-T7-Varp (RDB14334) pEF-HA-RACK1 (RDB14335) pEF-T7-RACK1 (RDB14336) pmStr-C1-RACK1 (RDB14337).