Defining bone fide effectors of RAS GTPases

Abstract

RAS GTPases play essential roles in normal development and are direct drivers of human cancers. Three decades of study have failed to wholly characterize pathways stimulated by activated RAS, driven by engagement with ‘effector’ proteins that have RAS binding domains (RBDs). Bone fide effectors must bind directly to RAS GTPases in a nucleotide‐dependent manner, and this interaction must impart a clear change in effector activity. Despite this, for most proteins currently deemed effectors there is little mechanistic understanding of how binding to the GTPase alters protein function. There has also been limited effort to comprehensively resolve the specificity of effector binding to the full array of RAS superfamily GTPase proteins. This review will summarize what is known about RAS‐driven activation for an array of potential effector proteins, focusing on structural and mechanistic effects and highlighting how little is still known regarding this key paradigm of cellular signal transduction.

Identification of an H-Ras nanocluster disrupting peptide

“…ASPP2 contains an RBD, interacts with oncogenic H-Ras and is a pan-Ras nanocluster scaffold that can neutralize Gal1 nanoclustering and can switch from a Gal1 promoted growth to a senescence phenotype 43 – 45 . Like the other RBD-containing proteins it was pulled down by L5UR-SNAP, as were its two RA-domain containing interaction partners, RASSF7 and RASSF9, which do not directly bind to Ras 5 , 46 . Quantification confirmed that the mutL5UR-SNAP was ≤50% more efficient than L5UR-SNAP in pulling down any of these proteins (Fig.…”

“…The two switch regions of GTP-Ras undergo significant conformational changes upon activation, thus enabling binding to the Ras binding domain (RBD) or Ras association (RA) domain of effectors, such as Raf, PI3Kα, and RASSF proteins. These effectors are implicated in cell proliferation, growth, and apoptosis, respectively 5 , 6 .…”