Cell-matrix mechanosensing and cellular metabolic demand are linked through SKT and mTORC2

Abstract

Integrin-based adhesion complexes mediate cell adhesion to the extracellular matrix and enable the cell to interpret and respond to both biochemical and mechanical cues. Such cues can affect a cells metabolic rate; however, how mechanical signals are converted into metabolic rate changes is not clear. We identified an uncharacterised protein; Sickle Tail Protein Homolog (KIAA1217), SKT to be enriched in cell-matrix adhesion complexes in stiff microenvironments. Low SKT expression correlates with an improved prognosis in pancreatic ductal adenocarcinoma (PDAC), suggesting an important role for SKT in extracellular matrix dependent tumour progression. Here, we show that SKT interacts with the mechanistic target of rapamycin complex 2 (mTORC2), a pivotal signalling complex in glucose metabolism, cell growth, and survival. SKT recruits mTORC2 to cell-matrix adhesions in a mechanoresponsive manner. SKT mediated mTORC2 signalling from adhesions is required for maintaining glycolytic flux and control of adhesion dynamics. Our findings show that SKT serves as a rheostat that controls metabolic adaptation of cells to their matrix microenvironment. Collectively, our research provides insights into the molecular mechanisms and interplay between cell adhesion and metabolic signalling in complex and stiff tumour microenvironments. The novel functions identified for SKT in cell-matrix adhesions, mTORC2 signalling and glycolysis unveils a signalling axis between the tumour microenvironment and cellular metabolism that are required for PDAC growth and invasion.