Agonist-stimulated phosphatidylinositol-3,4,5-trisphosphate generation by scaffolded phosphoinositide kinases

被引：92

作者：

Choi, Suyong ^{[1
]}

Hedman, Andrew C. ^{[2
]}

Sayedyahossein, Samar ^{[2
]}

Thapa, Narendra ^{[1
]}

Sacks, David B. ^{[2
]}

Anderson, Richard A. ^{[1
]}

机构：

[1] Univ Wisconsin, Sch Med & Publ Hlth, 1300 Univ Ave, Madison, WI 53706 USA

[2] NIH, Dept Lab Med, 10 Ctr Dr, Bethesda, MD 20892 USA

来源：

NATURE CELL BIOLOGY | 2016年 / 18卷 / 12期

基金：

美国国家卫生研究院;

关键词：

FOCAL ADHESION KINASE; PHOSPHATE KINASE; EXOCYST COMPLEX; BREAST-CANCER; LEADING-EDGE; CELL-LINE; IQGAP1; MEMBRANE; ACTIVATION; 3-KINASE;

D O I：

10.1038/ncb3441

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Generation of the lipid messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P-3) is crucial for development, cell growth and survival, and motility, and it becomes dysfunctional in many diseases including cancers. Here we reveal a mechanism for PtdIns(3,4,5)P-3 generation by scaffolded phosphoinositide kinases. In this pathway, class I phosphatidylinositol-3-OH kinase (PI(3)K) is assembled by IQGAP1 with PI(4)KIII alpha and PIPKI alpha, which sequentially generate PtdIns(3,4,5) P3 from phosphatidylinositol. By scaffolding these kinases into functional proximity, the PtdIns(4,5)P-2 generated is selectively used by PI(3)K for PtdIns(3,4,5)P-3 generation, which then signals to PDK1 and Akt that are also in the complex. Moreover, multiple receptor types stimulate the assembly of this IQGAP1-PI(3) K signalling complex. Blockade of IQGAP1 interaction with PIPKI alpha or PI(3)K inhibited PtdIns(3,4,5)P-3 generation and signalling, and selectively diminished cancer cell survival, revealing a target for cancer chemotherapy.

引用

页码：1324 / +

页数：59