Center for Medical Ethics and Health Policy Staff Publications

Language

English

Publication Date

9-20-2024

Journal

Science

DOI

10.1126/science.add8947

PMID

39298586

PMCID

PMC11811912

PubMedCentral® Posted Date

3-20-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gαi2, a key component in heterotrimeric G-protein signal transduction usually thought to regulate adenylyl cyclase-mediated cAMP production. Patients with activating Gαi2 mutations had clinical presentations that included impaired immunity. Mutant Gαi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gαi2 influenced TCR signaling by sequestering the GTPase-activating protein RASA2, thereby promoting RAS activation and increasing downstream ERK/MAPK and PI3K-AKT S6 signaling to drive cellular growth and proliferation.

Keywords

Humans, Cell Movement, Cell Proliferation, Germ-Line Mutation, GTP-Binding Protein alpha Subunit, Gi2, Immunity, MAP Kinase Signaling System, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, ras GTPase-Activating Proteins, ras Proteins, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Pedigree

Published Open-Access

yes

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