Kinase signaling cascades: An updated mechanistic landscape

Abstract

Here we shed physico-chemical light on major kinase signal transduction cascades in cell proliferation in the Ras network, MAPK and PI3K/AKT/mTOR. The cascades respond to external stimulus. The kinases are allosterically activated and relay the signal, leading to cell growth and division. The pathways are crosslinked, with the output of one pathway influencing the other. The effectiveness of their allosteric signaling relay stems from coordinated speed, and precision. These qualities are essential for cell life–yet exactly how they are gained and regulated have challenged the community over four decades. 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 dense molecular condensates 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 can we learn from their different number of mutations; and (iii) why B-Raf’s unique side-to-side inverse dimerization, which slows activation and ERK’s signaling. We point to the (iv) chemical mechanics of the distributions of rates of the crucial MAPK cascade: slower at the top; rapid at the bottom. Finally, we learn the cascades to inspire 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.