Open AccessCdc42 functions as a regulatory node for tumour‐derived microvesicle biogenesis
Author(s) -
Wang Jing,
Zhuang Xiangjin,
Greene Kai Su,
Si Ha,
Antonyak Marc A.,
Druso Joseph E.,
Wilson Kristin F.,
Cerione Richard A.,
Feng Qiyu,
Wang Hongyang
Publication year - 2021
Publication title -
journal of extracellular vesicles
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.94
H-Index - 68
ISSN - 2001-3078
DOI - 10.1002/jev2.12051
Subject(s) - microbiology and biotechnology , microvesicle , biogenesis , cdc42 , microvesicles , small gtpase , internalization , biology , escrt , effector , chemistry , signal transduction , endosome , cell , intracellular , microrna , biochemistry , gene
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, VEGF 90K , 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.