Membrane Recruitment as a Cancer Mechanism: A Case Study of Akt PH Domain.
Evidence from multiple laboratories has suggested the possibility that defective membrane recruitment, triggered by mutations in conserved lipid binding domains, could be a common molecular mechanism underlying carcinogenesis. Now a recent paper by Carpten et al. in Nature has identified and analyzed one such mutation; specifically, E17K in the lipid binding pocket of the Akt plextrin homology (PH domain). This study is a tour de force that (i) pinpoints a mutation widespread in human cancers, (ii) analyzes the effect of this mutation on lipid binding domain structure, (iii) shows that the mutation enhances plasma membrane recruitment, and (iv) demonstrates that such recruitment is linked to Akt pathway superactivation, cellular transformation and tumor formation. Overall, the work provides the most convincing illustration to date that a mutation altering the membrane docking of a lipid binding domain can directly trigger cancer. Furthermore, the findings raise intriguing questions regarding the mechanism by which the highly carcinogenic E17K mutation drives enhanced recruitment of the Akt PH domain to the plasma membrane.