Figure 2.

Intracellular mechanosensation pathways that accelerate glycolysis. (a) Cytoskeleton filaments and their dynamics. (b) Cell-cell adhesion forces are sensed through E-cadherin, which forms a complex with and activates liver kinase B1 (LKB1) as well as AMPK. AMPK and the membrane-cytoskeletal protein vinculin are phosphorylated by LKB1 and tyrosine-protein kinase Abl, respectively. Vinculin activity enhances actin remodelling through the Rho/ROCK pathway, whereas AMPK promotes glucose uptake and ATP production in order to maintain energy supply to adhesions. (c) Stimulation of receptor tyrosine kinases by growth factors activates PI3K, resulting in generation of PIP3, and recruitment and activation of GTP-Rac, which promotes actin fibre remodelling. (d) Cell-matrix forces are sensed through integrins in focal adhesion complexes, which promote actin remodelling through Rho/ROCK and JNK/p38 signaling. Actin fibre remodelling, integrates all three signaling pathways, and enhances transcriptional activity of YAP/TAZ as well as release of glycolytic enzymes in the cytosol. The cytoskeleton also sequesters TRIM21 from the cytosol, preventing proteasomal-mediated degradation of PFK. These processes culminate in acceleration of glucose metabolism.

FAK, focal adhesion kinase; MLC, myosin light chain; MLCK, myosin light-chain kinase; p38, P38 mitogen-activated protein kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; ROCK, Rho-associated kinase; RTK, receptor tyrosine kinase; Src, proto-oncogene tyrosine-protein kinase.