This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Focal adhesion kinase (FAK) is a key regulator of cell migration, proliferation and cell survival downstream of integrin and growth factor signaling. Its crucial physiological roles make FAK an important drug target. FAK is frequently overexpressed in a variety of tumors and a correlation between FAK overexpression and invasiveness was found in liver, colon, breast, ovarian and oral cancers.There is evidence from biochemistry and cell biology experiments that the N-terminal FERM domain directly interacts with the kinase domain and thereby downregulates catalytic activity.We have collected data on X29A that was used to solve the structure of a large fragment of FAK. The structure represents an autoinhibited conformation where the N-terminal FERM domain interacts with the catalytic kinase domain. The structure reveals a novel mode of kinase autoinhibition, where the FERM-kinase interaction protects regulatory tyrosines from being phosphorylated and blocks entry of a substrate to the active site. We have demonstrated by site-directed mutagenesis that if the interaction seen in the crystal structure is disrupted kinase activity is greatly increased and phosphorylation of regulatory tyrosines is accelerated. We are now aiming to solve an active form of FAK in complex with a substarte in order to understand the activation mechanism in more detail. The finding from the research carried out in this project will greatly improve the molecular understanding of FAK regulation and will provide a sound basis for the structure-guided design of FAK inhibitors. The development of FAK inhibitors is expected to yield potent anti-neoplastic or anti-metastatic drugs.
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