Cancer and Autism: How PTEN Mutations Degrade Function at the Membrane and Isoform Expression in the Human Brain

Hyunbum Jang, Jiaye Chen, Lilia M. Iakoucheva, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations causing loss of PTEN lipid phosphatase activity can promote cancer, benign tumors (PHTS), and neurodevelopmental disorders (NDDs). Exactly how they preferentially trigger distinct phenotypic outcomes has been puzzling. Here, we demonstrate that PTEN mutations differentially allosterically bias P loop dynamics and its connection to the catalytic site, affecting catalytic activity. NDD-related mutations are likely to sample conformations of the functional wild-type state, while sampled conformations for the strong, cancer-related driver mutation hotspots favor catalysis-primed conformations, suggesting that NDD mutations are likely to be weaker, and our large-scale simulations show why. Prenatal PTEN isoform expression data suggest exons 5 and 7, which harbor NDD mutations, as cancer-risk carriers. Since cancer requires more than a single mutation, our conformational and genomic analysis helps discover how same protein mutations can foster different clinical manifestations, articulates a role for co-occurring background latent driver mutations, and uncovers relationships of splicing isoform expression to life expectancy.

Original languageEnglish
Article number168354
JournalJournal of Molecular Biology
Volume435
Issue number24
DOIs
StatePublished - 15 Dec 2023

Funding

FundersFunder number
U.S. Government
National Institutes of HealthHHSN261201500003I
U.S. Department of Health and Human Services
National Cancer Institute
Center for Cancer Research

    Keywords

    • allosteric mutations
    • autism spectrum disorder
    • cancer
    • neurodevelopmental disorders
    • tumor suppressor

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