2. Academic Validation
  3. CNKSR1 serves as a scaffold to activate an EGFR phosphatase via exclusive interaction with RhoB-GTP

CNKSR1 serves as a scaffold to activate an EGFR phosphatase via exclusive interaction with RhoB-GTP

  • Life Sci Alliance. 2021 Jun 29;4(9):e202101095. doi: 10.26508/lsa.202101095.
Kanako Nishiyama 1 2,  Masashi Maekawa 3 4,  Tomoya Nakagita 5,  Jun Nakayama 6,  Takeshi Kiyoi 7,  Mami Chosei 4,  Akari Murakami 1,  Yoshiaki Kamei 1,  Hiroyuki Takeda 5,  Yasutsugu Takada 1,  Shigeki Higashiyama 8 4 9
Affiliations

Affiliations

  • 1 Department of Hepato-Biliary-Pancreatic Surgery and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan.
  • 2 Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan.
  • 3 Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan masashim@m.ehime-u.ac.jp.
  • 4 Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Japan.
  • 5 Division of Proteo-Drug-Discovery Sciences, Proteo-Science Center, Ehime University, Matsuyama, Japan.
  • 6 Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Japan.
  • 7 Division of Analytical Bio-medicine, Advanced Research Support Center, Ehime University, Toon, Japan.
  • 8 Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan shigeki@m.ehime-u.ac.jp.
  • 9 Department of Molecular and Cellular Biology, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan.
PMID: 34187934 DOI: 10.26508/lsa.202101095
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-128590
    98.50%, Mutant KRAS/Cnk1 抑制剂
    Ras
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