TGF-β-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion

被引：271

作者：

Lamouille, Samy ^{[1
]}

Connolly, Erin ^{[2
]}

Smyth, James W. ^{[3
]}

Akhurst, Rosemary J. ^{[2
,4
]}

Derynck, Rik ^{[1
,2
,4
,5
]}

机构：

[1] Univ Calif San Francisco, Dept Cell & Tissue Biol, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[3] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA

[4] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA

[5] Univ Calif San Francisco, Program Dev Biol, San Francisco, CA 94143 USA

来源：

JOURNAL OF CELL SCIENCE | 2012年 / 125卷 / 05期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR-BETA; AKT PHOSPHORYLATION; CANCER; RICTOR; METASTASIS; KINASE; MICE; CYTOSKELETON; RHOA; EMT;

D O I：

10.1242/jcs.095299

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

In cancer progression, carcinoma cells gain invasive behavior through a loss of epithelial characteristics and acquisition of mesenchymal properties, a process that can lead to epithelial-mesenchymal transition (EMT). TGF-beta is a potent inducer of EMT, and increased TGF-beta signaling in cancer cells is thought to drive cancer-associated EMT. Here, we examine the physiological requirement for mTOR complex 2 (mTORC2) in cells undergoing EMT. TGF-beta rapidly induces mTORC2 kinase activity in cells undergoing EMT, and controls epithelial cell progression through EMT. By regulating EMT-associated cytoskeletal changes and gene expression, mTORC2 is required for cell migration and invasion. Furthermore, inactivation of mTORC2 prevents cancer cell dissemination in vivo. Our results suggest that the mTORC2 pathway is an essential downstream branch of TGF-beta signaling, and represents a responsive target to inhibit EMT and prevent cancer cell invasion and metastasis.

引用

页码：1259 / 1273

页数：15

共 46 条

[1] Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism [J].

Bhowmick, NA ;

Ghiassi, M ;

Bakin, A ;

Aakre, M ;

Lundquist, CA ;

Engel, ME ;

Arteaga, CL ;

Moses, HL .

MOLECULAR BIOLOGY OF THE CELL, 2001, 12 (01) :27-36

[2] TGF-β and cancer [J].

Bierie, B ;

Moses, HL .

CYTOKINE & GROWTH FACTOR REVIEWS, 2006, 17 (1-2) :29-40

[3] TGFβ:: the molecular Jekyll and Hyde of cancer [J].

Bierie, Brian ;

Moses, Harold L. .

NATURE REVIEWS CANCER, 2006, 6 (07) :506-520

[4]

BURNS PA, 1991, ONCOGENE, V6, P2363

[5] Paxillin comes of age [J].

Deakin, Nicholas O. ;

Turner, Christopher E. .

JOURNAL OF CELL SCIENCE, 2008, 121 (15) :2435-2444

[6] Smad-dependent and Smad-independent pathways in TGF-β family signalling [J].

Derynck, R ;

Zhang, YE .

NATURE, 2003, 425 (6958) :577-584

[7] Specificity and versatility in TGF-β signaling through Smads [J].

Feng, XH ;

Derynck, R .

ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 2005, 21 :659-693

[8] TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation [J].

Fleming, Y. M. ;

Ferguson, G. J. ;

Spender, L. C. ;

Larsson, J. ;

Karlsson, S. ;

Ozanne, B. W. ;

Grosse, R. ;

Inman, G. J. .

ONCOGENE, 2009, 28 (07) :983-993

[9] mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s [J].

Frias, Maria A. ;

Thoreen, Carson C. ;

Jaffe, Jacob D. ;

Schroder, Wayne ;

Sculley, Tom ;

Carr, Steven A. ;

Sabatini, David M. .

CURRENT BIOLOGY, 2006, 16 (18) :1865-1870

[10] Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα but not S6K1 [J].

Guertin, David A. ;

Stevens, Deanna M. ;

Thoreen, Carson C. ;

Burds, Aurora A. ;

Kalaany, Nada Y. ;

Moffat, Jason ;

Brown, Michael ;

Fitzgerald, Kevin J. ;

Sabatini, David M. .

DEVELOPMENTAL CELL, 2006, 11 (06) :859-871

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