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
Recommended Citation
Ham, Hyoungjun; Jing, Huie; Lamborn, Ian T; et al., "Germline Mutations in a G Protein Identify Signaling Cross-Talk in T Cells" (2024). Center for Medical Ethics and Health Policy Staff Publications. 147.
https://digitalcommons.library.tmc.edu/med_ethics/147