Kindlin-2 links mechano-environment to proline synthesis and tumor growth

Guo, Ling1,2; Cui, Chunhong1,2; Zhang, Kuo1,2; Wang, Jiaxin1,2; Wang, Yilin1,2; Lu, Yixuan1,2; Chen, Ka3; Yuan, Jifan1,2; Xiao, Guozhi1,2,4; Tang, Bin1,2,5; Sun, Ying1,2; Wu, Chuanyue3

2019-02-19

10.1038/s41467-019-08772-3

Nature Communications   影响因子和分区

2041-1723

Cell metabolism is strongly influenced by mechano-environment. We show here that a fraction of kindlin-2 localizes to mitochondria and interacts with pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme for proline synthesis. Extracellular matrix (ECM) stiffening promotes kindlin-2 translocation into mitochondria and its interaction with PYCR1, resulting in elevation of PYCR1 level and consequent increase of proline synthesis and cell proliferation. Depletion of kindlin-2 reduces PYCR1 level, increases reactive oxygen species (ROS) production and apoptosis, and abolishes ECM stiffening-induced increase of proline synthesis and cell proliferation. In vivo, both kindlin-2 and PYCR1 levels are markedly increased in lung adenocarcinoma. Ablation of kindlin-2 in lung adenocarcinoma substantially reduces PYCR1 and proline levels, and diminishes fibrosis in vivo, resulting in marked inhibition of tumor growth and reduction of mortality rate. Our findings reveal a mechanoresponsive kindlin-2-PYCR1 complex that links mechano-environment to proline metabolism and signaling, and suggest a strategy to inhibit tumor growth.

SCI

英语

NI论文

第一 ; 通讯

Shenzhen Innovation Committee of Science and Technology[JCYJ20150831142427959] ; Shenzhen Innovation Committee of Science and Technology[ZDSYS20140509142721429]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000459056400002

NATURE PUBLISHING GROUP

Web of Science

1.Southern Univ Sci & Technol, Dept Biol, Shenzhen Key Lab Cell Microenvironm, Guangdong Prov Key Lab Cell Microenvironm & Dis R, Shenzhen 518055, Guangdong, Peoples R China
2.Southern Univ Sci & Technol, Acad Adv Interdisciplinary Studies, Shenzhen 518055, Guangdong, Peoples R China
3.Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA
4.Rush Univ, Med Ctr, Dept Orthoped Surg, Chicago, IL 60612 USA
5.Southern Univ Sci & Technol, Dept Biomed Engn, Shenzhen 518055, Guangdong, Peoples R China

Guo, Ling,Cui, Chunhong,Zhang, Kuo,et al. Kindlin-2 links mechano-environment to proline synthesis and tumor growth[J]. Nature Communications,2019,10.

Guo, Ling.,Cui, Chunhong.,Zhang, Kuo.,Wang, Jiaxin.,Wang, Yilin.,...&Wu, Chuanyue.(2019).Kindlin-2 links mechano-environment to proline synthesis and tumor growth.Nature Communications,10.

Guo, Ling,et al."Kindlin-2 links mechano-environment to proline synthesis and tumor growth".Nature Communications 10(2019).