The PIF-pocket regulatory site in AGC kinases: relevance for cellular physiology and innovative therapies
نویسنده
چکیده
The group of AGC protein kinases includes more than 60 protein kinases in the human genome (e.g. PDK1 and isoforms of PKA, PKC, PRK, PKB/Akt, S6K, SGK, RSK, MSK, ROCK, GRK, amongst others). This group is also widely represented in other eukaryotes, including organisms that cause human infectious diseases. Human AGC kinases are involved in diverse cellular functions and are potential targets for the treatment of cancer, diabetes, obesity, neurological disorders, inflammation, viral infections, etc. Small molecule inhibitors of AGC kinases can also be considered as potential candidates for the development of targeted therapies against infectious diseases. AGC kinases are typically regulated by phosphorylation at three sites, the activation loop, the Zipper/turn-motif and the hydrophobic motif sites, and by other diverse mechanisms including intramolecular interactions with other regions of the protein, oligomerization, interaction with regulatory subunits, and second messengers. Interestingly, we were able to identify that a particular pocket on the kinase domain, termed the PIF-pocket, is a key mediator of the allosteric regulation of many AGC kinases. We first described the regulatory properties of the PIF-pocket on PDK1 [1]. Follow-up work verified that the PIF-pocket is also the key site that mediates the activation by Zipper/ turn-motif and hydrophobic motif phosphorylation of PKB/Akt, S6K, RSK, SGK, PKC, PRK, and MSK [2–4]. Interaction with the PIF-pocket also regulates the intramolecular inhibition of atypical PKCs by their N-terminal domains [5] and the oligomerization that inhibits PRK2 [6]. Moreover, we have developed reversible low-molecular-weight compounds that, by targeting the PIF-pocket site, allosterically activate PDK1 [7, 8], or allosterically inhibit atypical PKCs [5]. Our studies have shed light on the molecular details of the mechanism of allosteric regulation by small compounds and support the future development of drugs directed to the PIF-pocket of AGC kinases. The PIF-pocket regulatory site shares similar features with a dimerization regulatory site recently discovered on receptor tyrosine kinases, suggesting that the deep Invited Lectures
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