Force For Activation


Tumor invasion and metastasis are major problems in the therapy of cancer patients. A team of researchers at the Heidelberg Institute of Theoretical Studies (HITS), the LMU Munich (both Germany) and the CNIO Madrid, Spain, has now elucidated the activation conditions for a key enzyme in this process – a step forward in the development of new therapeutic strategies.

To develop strategies of active tumor metastasis prevention, clarification of the underlying activation process is necessary. Focal adhesion kinase (FAK) is one key enzyme involved in the signaling cascade of cancer invasion and metastasis. This makes it a promising target for cancer therapeutics.

Scientists at the Heidelberg Institute for Theoretical Studies /HITS), led by Professor Frauke Gräter and collaboration partners at the LMU Munich around Professor Hermann Gaub and at the Spanish National Cancer Research Centre (CNIO)  in Madrid around Professor Daniel Lietha  now elucidated the force-mediated activation process of FAK and present their results in the journal Proceedings of the National Academy of Sciences of the Unites States of America (PNAS).

What’s the trigger?

As signaling protein, FAK regulates the essential processes of a cell: adhesion, migration and survival. These kinase proteins are localized at the cytoplasmic site of focal adhesion complexes, figuratively the feet of the cells.

“In the non-active state, the focal adhesion kinase is auto-inhibited and inactive with the active center hidden by a protein lid,” explains Magnus Bauer, first author of the publication and NIM-GP graduate student at the LMU. “Our aim was to examine whether mechanical force can open that lid and thereby trigger activation of this key player by inducing conformational changes.”

This is of special interest as in pathological situations, activated FAK also promotes adhesion to tumor tissue and the extracellular matrix – required for tumor cell invasion and spreading of metastases. In addition, its overexpression in cancer cells results in the inhibition of natural cell death and downregulation of the tumor suppressor gene p53.