Linking E-cadherin mechanotransduction to cell metabolism through force-mediated activation of AMPK

Abstract

The response of cells to mechanical force is a major determinant of cell behavior and is an energetically costly event. How cells derive energy to resist mechanical force is unknown. Here, we show that application of force to E-cadherin stimulates Liver Kinase B1 (LKB1) to activate AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis. LKB1 recruits AMPK to the E-cadherin mechanotransduction complex, thereby stimulating actomyosin contractility, glucose uptake, and ATP production. The increase in ATP provides energy to reinforce the adhesion complex and actin cytoskeleton so the cell can resist physiological forces. Together, these findings reveal a paradigm for how mechanotransduction and metabolism are linked and provide a framework for understanding how diseases involving contractile and metabolic disturbances arise.

Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy

“…Increasing evidences suggest a central connection of mechanotransduction – including the YAP/TAZ pathway – with cellular metabolism (Santinon et al, 2018; Yang et al, 2018), and processes related to glucose consumption and Warburg metabolism (Bays et al, 2017; Enzo et al, 2015; Mo et al, 2015; Sorrentino et al, 2014; Wang et al, 2015). However, increased glycolysis alone is insufficient to meet the total metabolic demands of proliferating cells.…”

It takes energy to resist force

“…2 Application of force increases co-localization and co-immunoprecipitation of LKB1 with E-cadherin. 1 When LKB1 is inhibited, forceinduced AMPK activation and recruitment to the cadherins is blocked. Hence, LKB1 mediates AMPK recruitment and activation at cell-cell contacts.…”

“…4,5 Our studies reveal a 2.0-fold increase in E-cadherin deposition in cell-cell junctions and a 3.8-fold increase in junctional actin. 1 Cells require both AMPK and increased ATP production to support the cytoskeletal changes necessary for cell stiffening. Hence, not only does forceinduced AMPK stimulate glucose uptake and increased contractility, but also the energy is used to support elevated tension.…”

“…In response to force on E-cadherin, we observe increased glucose uptake in 2 cell lines in response to multiple forces. 1 The glucose uptake requires increased contractility and E-cadherin expression. Also of note, the glucose taken up into the cell was converted to ATP.…”

“…1 Specifically, application of shear stress or tensile force to E-cadherin on 2 different epithelial cell lines triggers activation of AMP-dependent kinase (AMPK, Fig. 1).…”