Kinase signaling cascades: an updated mechanistic landscape
Ruth Nussinov, Clil Regev, Hyunbum Jang
Abstract
. Here, we define their nature by their kinases' repertoires, substrate specificities and breadth, activation and autoinhibition mechanisms, catalytic rates, interactions, and their dilution state. The cascades are lodged in a dense molecular condensate phase at the membrane adjoining RTK clusters, where their assemblies promote specific, productive signaling. Aiming to shed further physico-chemical light, we ask (i) how starting the cascades with a single substrate and ending with hundreds is still labeled specific; (ii) what we can learn from their different number of mutations; and (iii) why B-Raf unique side-to-side inverse dimerization slows ERK activation and signaling. We point to the (iv) chemical mechanics of the distributions of rates of the crucial MAPK cascade: slower at the top and rapid at the bottom. Finally, the cascades provide inspiration for pharmacological perspectives. Collectively, our updated physico-chemical outlook provides the molecular basis of targeting protein kinases in cancer and spans mechanisms and scales, from conformational landscapes to membraneless organelles, cells and systems levels.