How signaling pathways link extracellular mechano-environment to proline biosynthesis: A hypothesis PINCH-1 and kindlin-2 sense mechanical signals from extracellular matrix and link them to proline biosynthesis

Chen, Keng1; Guo, Ling2,3; Wu, Chuanyue4

2021-07-01

10.1002/bies.202100116

BIOESSAYS   影响因子和分区

0265-9247

1521-1878

We propose a signaling pathway in which cell-extracellular matrix (ECM) adhesion components PINCH-1 and kindlin-2 sense mechanical signals from ECM and link them to proline biosynthesis, a vital metabolic pathway for macromolecule synthesis, redox balance, and ECM remodeling. ECM stiffening promotes PINCH-1 expression via integrin signaling, which suppresses dynamin-related protein 1 (DRP1) expression and mitochondrial fission, resulting in increased kindlin-2 translocation into mitochondria and interaction with Delta(1)-pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1). Kindlin-2 interaction with PYCR1 protects the latter from proteolytic degradation, leading to elevated PYCR1 level. Additionally, PINCH-1 promotes P5C synthase (P5CS) expression and P5C synthesis, which, together with increased PYCR1 level, support augmented proline biosynthesis. This signaling pathway is frequently activated in fibrosis and cancer, resulting in increased proline biosynthesis and excessive collagen matrix production, which in turn further promotes ECM stiffening. Targeting this signaling pathway, therefore, may provide an effective strategy for alleviating fibrosis and cancer progression.

cancer collagen extracellular mechano-environment fibrosis focal adhesion proteins mitochondrial dynamics proline biosynthesis

SCI

英语

其他

National Key R&D Program of China[2019YFA0906000] ; National Natural Science Foundation of China[31701194] ; Natural Science Foundation of Guangdong Province[2017B030301018] ; Shenzhen Innovation Committee of Science and Technology["JCYJ20190809115017189","JCYJ20180302174228311","ZDSYS20140509142721429"]

Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics

Biochemistry & Molecular Biology ; Biology

WOS:000669261300001

WILEY

BIOLOGY & BIOCHEMISTRY

Web of Science

1.Greater Bay Biomed InnoCtr, Shenzhen Bay Lab, Shenzhen, Peoples R China
2.Southern Univ Sci & Technol, Dept Biol, Guangdong Prov Key Lab Cell Microenvironm & Dis R, Shenzhen, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen Key Lab Cell Microenvironm, Shenzhen, Peoples R China
4.Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA

Chen, Keng,Guo, Ling,Wu, Chuanyue. How signaling pathways link extracellular mechano-environment to proline biosynthesis: A hypothesis PINCH-1 and kindlin-2 sense mechanical signals from extracellular matrix and link them to proline biosynthesis[J]. BIOESSAYS,2021.

Chen, Keng,Guo, Ling,&Wu, Chuanyue.(2021).How signaling pathways link extracellular mechano-environment to proline biosynthesis: A hypothesis PINCH-1 and kindlin-2 sense mechanical signals from extracellular matrix and link them to proline biosynthesis.BIOESSAYS.

Chen, Keng,et al."How signaling pathways link extracellular mechano-environment to proline biosynthesis: A hypothesis PINCH-1 and kindlin-2 sense mechanical signals from extracellular matrix and link them to proline biosynthesis".BIOESSAYS (2021).