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Publication : Germline mutations in a G protein identify signaling cross-talk in T cells.

First Author  Ham H Year  2024
Journal  Science Volume  385
Issue  6715 Pages  eadd8947
PubMed ID  39298586 Mgi Jnum  J:378730
Mgi Id  MGI:7737743 Doi  10.1126/science.add8947
Citation  Ham H, et al. (2024) Germline mutations in a G protein identify signaling cross-talk in T cells. Science 385(6715):eadd8947
abstractText  Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes G(alphai2), 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(alphai2) mutations had clinical presentations that included impaired immunity. Mutant G(alphai2) impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G(alphai2) 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.
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