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Ham, H.* ; Jing, H.* ; Lamborn, I.T.* ; Kober, M.M.* ; Koval, A.* ; Berchiche, Y.A.* ; Anderson, D.E.* ; Druey, K.M.* ; Mandl, J.N.* ; Isidor, B.* ; Ferreira, C.R.* ; Freeman, A.F.* ; Ganesan, S.* ; Karsak, M.* ; Mustillo, P.J.* ; Teo, J.* ; Zolkipli-Cunningham, Z.* ; Chatron, N.* ; Lecoquierre, F.* ; Oler, A.J.* ; Schmid, J.P.* ; Kuhns, D.B.* ; Xu, X.* ; Hauck, F.* ; Al-Herz, W.* ; Wagner, M. ; Terhal, P.A.* ; Muurinen, M.* ; Barlogis, V.* ; Cruz, P.* ; Danielson, J.* ; Stewart, H.* ; Loid, P.* ; Rading, S.* ; Keren, B.* ; Pfundt, R.* ; Zarember, K.A.* ; Vill, K.* ; Potocki, L.* ; Olivier, K.N.* ; Lesca, G.* ; Faivre, L.* ; Wong, M.* ; Puel, A.* ; Chou, J.* ; Tusseau, M.* ; Moutsopoulos, N.M.* ; Matthews, H.F.* ; Simons, C.* ; Taft, R.J.* ; Soldatos, A.* ; Masle-Farquhar, E.* ; Pittaluga, S.* ; Brink, R.* ; Fink, D.L.* ; Kong, H.H.* ; Kabat, J.* ; Kim, W.S.* ; Bierhals, T.* ; Meguro, K.* ; Hsu, A.P.* ; Gu, J.* ; Stoddard, J.* ; Banos-Pinero, B.* ; Slack, M.* ; Trivellin, G.* ; Mazel, B.* ; Soomann, M.* ; Li, S.* ; Watts, V.J.* ; Stratakis, C.A.* ; Rodriguez-Quevedo, M.F.* ; Bruel, A.L.* ; Lipsanen-Nyman, M.* ; Saultier, P.* ; Jain, R.* ; Lehalle, D.* ; Torres, D.* ; Sullivan, K.E.* ; Barbarot, S.* ; Neu, A.* ; Duffourd, Y.* ; Similuk, M.* ; McWalter, K.* ; Blanc, P.D.* ; Bézieau, S.* ; Jin, T.* ; Geha, R.S.* ; Casanova, J.L.* ; Mäkitie, O.M.* ; Kubisch, C.* ; Edery, P.* ; Christodoulou, J.* ; Germain, R.N.* ; Goodnow, C.C.* ; Sakmar, T.P.* ; Billadeau, D.D.* ; Küry, S.* ; Katanaev, V.L.* ; Zhang, Y.* ; Lenardo, M.J.* ; Su, H.C.*

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

Science 385:eadd8947 (2024)
Publ. Version/Full Text Postprint DOI PMC
Open Access Green
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 cyclic adenosine monophosphate (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 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Adenylyl-cyclase; Crystal-structure; Alpha-subunit; Activation; Beta; Inhibition; Mechanism; Binding; Impact; Ras
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0036-8075
e-ISSN 1095-9203
Journal Science
Quellenangaben Volume: 385, Issue: 6715, Pages: , Article Number: eadd8947 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
DOI 10.1126/science.add8947
WOS ID 001325254300001
Scopus ID 85204512765
PubMed ID 39298586
Erfassungsdatum 2024-10-29
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