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

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.
Authors	Ling Guo, Chunhong Cui, Kuo Zhang, Jiaxin Wang, Yilin Wang, Yixuan Lu, Ka Chen, Jifan Yuan, Guozhi Xiao, Bin Tang, Ying Sun, Chuanyue Wu
Journal	Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 845 (02 19 2019) ISSN: 2041-1723 [Electronic] England
PMID	30783087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cytoskeletal Proteins FERMT3 protein, human Membrane Proteins Muscle Proteins Neoplasm Proteins kindlin-2 protein, mouse Proline PYCR2 protein, human Pyrroline Carboxylate Reductases
Topics	A549 Cells Adenocarcinoma of Lung (metabolism, pathology) Animals Cell Proliferation (physiology) Cell Survival (physiology) Cytoskeletal Proteins (genetics, metabolism) Extracellular Matrix (genetics, metabolism) Female Humans Lung Neoplasms (metabolism, pathology) Male Membrane Proteins (genetics, metabolism) Mice, Transgenic Mitochondria (metabolism) Muscle Proteins (genetics, metabolism) Neoplasm Proteins (genetics, metabolism) Proline (biosynthesis) Pyrroline Carboxylate Reductases (genetics, metabolism) delta-1-Pyrroline-5-Carboxylate Reductase

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