A direct role for Met endocytosis in tumorigenesis

被引：189

作者：

Joffre, Carine ^{[1
]}

Barrow, Rachel ^{[1
]}

Menard, Ludovic ^{[1
]}

Calleja, Veronique ^{[2
]}

Hart, Ian R.

Kermorgant, Stephanie ^{[1
]}

机构：

[1] Queen Mary Univ London, Barts Canc Inst, Tumor Biol Ctr, Spatial Signalling Team,John Vane Sci Ctr, London EC1M 6BQ, England

[2] London Res Inst, Canc Res UK, Cell Biophys Lab, London WC2A 3PX, England

来源：

NATURE CELL BIOLOGY | 2011年 / 13卷 / 07期

基金：

英国医学研究理事会;

关键词：

TYROSINE KINASE; C-MET; SIGNAL-TRANSDUCTION; CELL-MIGRATION; EGF RECEPTOR; ENDOPLASMIC-RETICULUM; MEDIATED ENDOCYTOSIS; SPATIAL RESTRICTION; SOMATIC MUTATIONS; HUMAN CANCER;

D O I：

10.1038/ncb2257

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Compartmentalization of signals generated by receptor tyrosine kinase (RTK) endocytosis has emerged as a major determinant of various cell functions. Here, using tumour-associated Met-activating mutations, we demonstrate a direct link between endocytosis and tumorigenicity. Met mutants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes, activation oft he GTPase Rac1, loss of actin stress fibres and increased levels of cell migration. Blocking endocytosis inhibited mutants' anchorage-independent growth, in vivo tumorigenesis and metastasis while maintaining their activation. One mutant resistant to inhibition by a Met-specific tyrosine kinase inhibitor was sensitive to endocytosis inhibition. Thus, oncogenicity of Met mutants results not only from activation but also from their altered endocytic trafficking, indicating that endosomal signalling may be a crucial mechanism regulating RTK-dependent tumorigenesis.

引用

页码：827 / U227

页数：23

共 57 条

[1] Spatial restriction of receptor tyrosine kinase activity through a polarized endocytic cycle controls border cell migration [J].