FAK controls the mechanical activation of YAP, a transcriptional regulator required for durotaxis

Abstract

Focal adhesion kinase (FAK) is a key molecule in focal adhesions and regulates fundamental processes in cells such as growth, survival, and migration. FAK is one of the first molecules recruited to focal adhesions in response to external mechanical stimuli and therefore is a pivotal mediator of cell mechanosignaling, and relays these stimuli to other mechanotransducers within the cytoplasm. Yes-associated protein (YAP) has been identified recently as one of these core mechanotransducers. YAP translocates to the nucleus following changes in cell mechanics to promote the expression of genes implicated in motility, apoptosis, proliferation, and organ growth. Here, we show that FAK controls the nuclear translocation and activation of YAP in response to mechanical activation and submit that the YAP-dependent process of durotaxis requires a cell with an asymmetric distribution of active and inactive FAK molecules.-Lachowski, D., Cortes, E., Robinson, B., Rice, A., Rombouts, K., Del Río Hernández, A. E. FAK controls the mechanical activation of YAP, a transcriptional regulator required for durotaxis.

Retinoic Acid Receptor‐β Is Downregulated in Hepatocellular Carcinoma and Cirrhosis and Its Expression Inhibits Myosin‐Driven Activation and Durotaxis in Hepatic Stellate Cells

“…We have previously reported that HSCs can perform rigidity gradient directed movement toward a stiffer substrate, also known as durotaxis . We used a dual‐rigidity gradient gel to determine whether ATRA can inhibit the ability of HSCs to exhibit durotaxis.…”

“…Mutually activating bidirectional crosstalk between hepatocytes and HSCs is known to promote a tumor‐permissive microenvironment, and directed migration of HSCs to the tumor augments this crosstalk and HCC progression . We have recently shown that durotaxis is another mechanism by which HSCs can be recruited to the fibrotic site, with directed migration via a stiffness gradient . Furthermore, the stiff environment generated by activated HSCs can recruit yet more HSCs through durotaxis, leading to accumulation .…”

“…The methodology for traction forces, atomic force microscopy (AFM), mechanosensing, functional/remodeling assay, and durotaxis followed previously reported procedures . A complete description can be found in Supporting methods information.…”

“…(15) Durotaxis, the process of directed migration based on substrate rigidity, has been observed in HSCs, and is suggested to lead to accumulation of HSCs and further potentiation of fibrosis as migrating HSCs become activated by the stiff environment. (16) The retinoic acid receptor family is known to modulate the function of HSCs, though the molecular mechanisms behind this regulation are not well understood. Elucidating the molecular events underlying HSC activation holds the key to blocking progression of early and advanced liver diseases.…”

“…In addition, HSCs have been shown to infiltrate into the tumor stroma and localize around the cancer cells, facilitating paracrine signaling . Durotaxis, the process of directed migration based on substrate rigidity, has been observed in HSCs, and is suggested to lead to accumulation of HSCs and further potentiation of fibrosis as migrating HSCs become activated by the stiff environment …”