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Nat Commun. 2019 Feb 19;10(1):845. doi: 10.1038/s41467-019-08772-3.

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

Author information

1
Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Department of Biology and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China. guol@sustc.edu.cn.
2
Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Department of Biology and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
3
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15261, USA.
4
Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois 60612, USA.
5
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
6
Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Department of Biology and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China. suny@sustc.edu.cn.
7
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15261, USA. carywu@pitt.edu.

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.

PMID:
30783087
PMCID:
PMC6381112
DOI:
10.1038/s41467-019-08772-3
[Indexed for MEDLINE]
Free PMC Article

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