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) |