Cdc42 functions as a regulatory node for tumour-derived microvesicle biogenesis.
Cdc42 functions as a regulatory node for tumour-derived microvesicle biogenesis.
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Cdc42 作为肿瘤源性微泡生物发生的调节节点
DOI：
10.1002/jev2.12051
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发表时间：
2021-01
影响因子：
16
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Wang J;Zhuang X;Greene KS;Si H;Antonyak MA;Druso JE;Wilson KF;Cerione RA;Feng Q;Wang H
肿瘤源性微泡（MV）是肿瘤微环境中细胞间通讯的关键介质。到目前为止，MV生物发生的潜在机制，特别是关键的肿瘤发生信号，如异常EGF信号调节MV释放，仍然不清楚。在这里，我们着手建立可靠的读出MV生物发生，然后探索调节MV生成的分子机制。我们发现Rho家族小G蛋白Cdc42是MV生物发生中多种调控信号的汇聚节点。激活的GTP结合Cdc42及其下游效应物Ras GTP活化样蛋白1（IQGAP 1）的结合是MV脱落所必需的。活化的Cdc42通过抑制细胞表面受体（包括EGFR和VEGF寡聚体VEGF 90 K）的内化来维持持续的EGF信号传导，然后促进MV释放。随后，我们进一步证明，使用相应的突变体阻断这些信号传导途径可有效减少MV脱落，并显著抑制MV促进的体内肿瘤血管生成。这些发现揭示了肿瘤细胞对MV脱落的复杂调控，揭示了MV生物发生的调控机制，并可能有助于癌症治疗中靶向MV的策略。
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.
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影响因子：
64.5
作者：
Fukata, M;Watanabe, T;Kaibuchi, K
通讯作者：
Kaibuchi, K
DOI：
10.1083/jcb.200802081
发表时间：
2008-06-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fackler OT;Grosse R
通讯作者：
Grosse R
前缘的内吞膜转换是由Cdc42和Graf1之间的瞬时相互作用驱动的。
影响因子：
4
作者：
Francis MK;Holst MR;Vidal-Quadras M;Henriksson S;Santarella-Mellwig R;Sandblad L;Lundmark R
通讯作者：
Lundmark R
影响因子：
8
作者：
Li, B.;Antonyak, M. A.;Zhang, J.;Cerione, R. A.
通讯作者：
Cerione, R. A.
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D