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Phosphorylation and Driver Mutations in PI3Kα and PTEN Autoinhibition.

ABSTRACT: PI3K and PTEN are the second and third most highly mutated proteins in cancer following only p53. Their actions oppose each other. PI3K phosphorylates signaling lipid PIP₂ to PIP₃ PTEN dephosphorylates it back. Driver mutations in both proteins accrue PIP₃ PIP₃ recruits AKT and PDK1 to the membrane, promoting cell-cycle progression. Here we review phosphorylation events and mutations in autoinhibition in PI3K and PTEN from the structural standpoint. Our purpose is to clarify how they control the autoinhibited states. In autoinhibition, a segment or a subunit of the protein occludes its functional site. Protein-protein interfaces are often only marginally stable, making them sensitive to changes in conditions in living cells. Phosphorylation can stabilize or destabilize the interfaces. Driver mutations commonly destabilize them. In analogy to "passenger mutations," we coin "passenger phosphorylation" to emphasize that the presence of a phosphorylation recognition sequence logo does not necessarily imply function. Rather, it may simply reflect a statistical occurrence. In both PI3K and PTEN, autoinhibiting phosphorylation events are observed in the occluding "piece." In PI3Kα, the "piece" is the p85α subunit. In PTEN, it is the C-terminal segment. In both enzymes the stabilized interface covers the domain that attaches to the membrane. Driver mutations that trigger rotation of the occluding piece or its deletion prompt activation. To date, both enzymes lack specific, potent drugs. We discuss the implications of detailed structural and mechanistic insight into oncogenic activation and how it can advance allosteric precision oncology.

SUBMITTER: Nussinov R

PROVIDER: S-EPMC8026595 | biostudies-literature |

REPOSITORIES: biostudies-literature

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