RRC ID 81311
Author Nishiyama K, Maekawa M, Nakagita T, Nakayama J, Kiyoi T, Chosei M, Murakami A, Kamei Y, Takeda H, Takada Y, Higashiyama S.
Title CNKSR1 serves as a scaffold to activate an EGFR phosphatase via exclusive interaction with RhoB-GTP.
Journal Life Sci Alliance
Abstract Epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) phosphorylation drives HER2-positive breast cancer cell proliferation. Enforced activation of phosphatases for those receptors could be a therapeutic option for HER2-positive breast cancers. Here, we report that degradation of an endosomal small GTPase, RhoB, by the ubiquitin ligase complex cullin-3 (CUL3)/KCTD10 is essential for both EGFR and HER2 phosphorylation in HER2-positive breast cancer cells. Using human protein arrays produced in a wheat cell-free protein synthesis system, RhoB-GTP, and protein tyrosine phosphatase receptor type H (PTPRH) were identified as interacting proteins of connector enhancer of kinase suppressor of Ras1 (CNKSR1). Mechanistically, constitutive degradation of RhoB, which is mediated by the CUL3/KCTD10 E3 complex, enabled CNKSR1 to interact with PTPRH at the plasma membrane resulting in inactivation of EGFR phosphatase activity. Depletion of CUL3 or KCTD10 led to the accumulation of RhoB-GTP at the plasma membrane followed by its interaction with CNKSR1, which released activated PTPRH from CNKSR1. This study suggests a mechanism of PTPRH activation through the exclusive binding of RhoB-GTP to CNKSR1.
Volume 4(9)
Published 2021-9-1
DOI 10.26508/lsa.202101095
PII 4/9/e202101095
PMID 34187934
PMC PMC8321701
MeSH Adult Aged Aged, 80 and over Breast Neoplasms / etiology Breast Neoplasms / metabolism Breast Neoplasms / pathology Carrier Proteins Cell Line, Tumor Cullin Proteins / metabolism ErbB Receptors / agonists ErbB Receptors / genetics ErbB Receptors / metabolism Female Gene Expression Regulation, Neoplastic Humans Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism* Middle Aged Models, Biological Phosphorylation Potassium Channels, Voltage-Gated / metabolism Prognosis Protein Array Analysis Protein Binding Proteolysis Receptor, ErbB-2 / genetics Receptor, ErbB-2 / metabolism Receptor-Like Protein Tyrosine Phosphatases, Class 3 / metabolism rhoB GTP-Binding Protein / metabolism*
Resource
DNA material CSII-CMV-MCS-IRES2-Bsd (RDB04385) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (REB04394)