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

Ling Guo (), Chunhong Cui, Kuo Zhang, Jiaxin Wang, Yilin Wang, Yixuan Lu, Ka Chen, Jifan Yuan, Guozhi Xiao, Bin Tang, Ying Sun () and Chuanyue Wu ()
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Ling Guo: Southern University of Science and Technology
Chunhong Cui: Southern University of Science and Technology
Kuo Zhang: Southern University of Science and Technology
Jiaxin Wang: Southern University of Science and Technology
Yilin Wang: Southern University of Science and Technology
Yixuan Lu: Southern University of Science and Technology
Ka Chen: University of Pittsburgh School of Medicine
Jifan Yuan: Southern University of Science and Technology
Guozhi Xiao: Southern University of Science and Technology
Bin Tang: Southern University of Science and Technology
Ying Sun: Southern University of Science and Technology
Chuanyue Wu: University of Pittsburgh School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-20

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08772-3

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