Germline mutations in a G protein identify signaling cross-talk in T cells.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39298586.
- Also identified by DOI 10.1126/science.add8947 and PMC identifier 11811912.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in <i>GNAI2</i>, which encodes G<sub>αi2</sub>, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G<sub>αi2</sub> mutations had clinical presentations that included impaired immunity. Mutant G<sub>αi2</sub> impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G<sub>αi2</sub> influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.
Medical subject headings
- Germ-Line Mutation
- GTP-Binding Protein alpha Subunit, Gi2
- ras GTPase-Activating Proteins
- Receptors, Antigen, T-Cell
- T-Lymphocytes