1. Academic Validation
  2. Cdc42 functions as a regulatory node for tumour-derived microvesicle biogenesis

Cdc42 functions as a regulatory node for tumour-derived microvesicle biogenesis

  • J Extracell Vesicles. 2021 Jan;10(3):e12051. doi: 10.1002/jev2.12051.
Jing Wang 1 2 Xiangjin Zhuang 1 2 Kai Su Greene 3 Ha Si 2 4 Marc A Antonyak 3 Joseph E Druso 3 Kristin F Wilson 3 Richard A Cerione 3 5 Qiyu Feng 1 2 Hongyang Wang 1 2
Affiliations

Affiliations

  • 1 Cancer Research Center The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui China.
  • 2 National Center for Liver Cancer Eastern Hepatobiliary Surgery Hospital/Institute the Second Military Medical University Shanghai China.
  • 3 Department of Molecular Medicine Cornell University Ithaca New York USA.
  • 4 Affiliated Hospital of Inner Mongolia University for the Nationalities Tongliao Inner Mongolia China.
  • 5 Department of Chemistry and Chemical Biology Cornell University Ithaca New York USA.
Abstract

Tumour-derived microvesicles (MVs) serve as critical mediators of cell-to-cell communication in the tumour microenvironment. So far, the underlying mechanisms of MV biogenesis, especially how key tumorigenesis signals such as abnormal EGF signalling regulates MV release, remain unclear. Here, we set out to establish reliable readouts for MV biogenesis and then explore the molecular mechanisms that regulate MV generation. We found that Rho family small G protein Cdc42 is a convergent node of multiple regulatory signals that occur in MV biogenesis. The binding of activated GTP-bound Cdc42 and its downstream effector, Ras GTPase-activating-like protein 1 (IQGAP1), is required for MV shedding. Activated Cdc42 maintains sustained EGF signalling by inhibiting the internalization of cell surface receptors, including EGFR and the VEGF oligomer, VEGF90K, and then facilitates MV release. Subsequently, we further demonstrated that blocking these signalling pathways using the corresponding mutants effectively reduced MV shedding and significantly inhibited MV-promoted in vivo tumour angiogenesis. These findings reveal a complex regulation of MV shedding by tumour cells, shedding LIGHT on the regulatory mechanism of MV biogenesis, and potentially contributing to strategies that target MVs in Cancer therapy.

Keywords

Cdc42; EGF signalling; GTPase; IQGAP; Microvesicle; tumour angiogenesis.

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    ≥99.0%, 网格蛋白介导的内吞抑制剂