Germline mutations in a G protein identify signaling cross-talk in T cells
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Germline mutations in a G protein identify signaling cross-talk in T cells. / Ham, Hyoungjun; Jing, Huie; Lamborn, Ian T; Kober, Megan M; Koval, Alexey; Berchiche, Yamina A; Anderson, D Eric; Druey, Kirk M; Mandl, Judith N; Isidor, Bertrand; Ferreira, Carlos R; Freeman, Alexandra F; Ganesan, Sundar; Karsak, Meliha; Mustillo, Peter J; Teo, Juliana; Zolkipli-Cunningham, Zarazuela; Chatron, Nicolas; Lecoquierre, François; Oler, Andrew J; Schmid, Jana Pachlopnik; Kuhns, Douglas B; Xu, Xuehua; Hauck, Fabian; Al-Herz, Waleed; Wagner, Matias; Terhal, Paulien A; Muurinen, Mari; Barlogis, Vincent; Cruz, Phillip; Danielson, Jeffrey; Stewart, Helen; Loid, Petra; Rading, Sebastian; Keren, Boris; Pfundt, Rolph; Zarember, Kol A; Vill, Katharina; Potocki, Lorraine; Olivier, Kenneth N; Lesca, Gaetan; Faivre, Laurence; Wong, Melanie; Puel, Anne; Chou, Janet; Tusseau, Maud; Moutsopoulos, Niki M; Matthews, Helen F; Simons, Cas; Taft, Ryan J; Soldatos, Ariane; Masle-Farquhar, Etienne; Pittaluga, Stefania; Brink, Robert; Fink, Danielle L; Kong, Heidi H; Kabat, Juraj; Kim, Woo Sung; Bierhals, Tatjana; Meguro, Kazuyuki; Hsu, Amy P; Gu, Jingwen; Stoddard, Jennifer; Banos-Pinero, Benito; Slack, Maria; Trivellin, Giampaolo; Mazel, Benoît; Soomann, Maarja; Li, Samuel; Watts, Val J; Stratakis, Constantine A; Rodriguez-Quevedo, Maria F; Bruel, Ange-Line; Lipsanen-Nyman, Marita; Saultier, Paul; Jain, Rashmi; Lehalle, Daphne; Torres, Daniel; Sullivan, Kathleen E; Barbarot, Sébastien; Neu, Axel; Duffourd, Yannis; Similuk, Morgan; McWalter, Kirsty; Blanc, Pierre; Bézieau, Stéphane; Jin, Tian; Geha, Raif S; Casanova, Jean-Laurent; Makitie, Outi M; Kubisch, Christian; Edery, Patrick; Christodoulou, John; Germain, Ronald N; Goodnow, Christopher C; Sakmar, Thomas P; Billadeau, Daniel D; Küry, Sébastien; Katanaev, Vladimir L; Zhang, Yu; Lenardo, Michael J; Su, Helen C.
In: SCIENCE, Vol. 385, No. 6715, 20.09.2024, p. eadd8947.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Germline mutations in a G protein identify signaling cross-talk in T cells
AU - Ham, Hyoungjun
AU - Jing, Huie
AU - Lamborn, Ian T
AU - Kober, Megan M
AU - Koval, Alexey
AU - Berchiche, Yamina A
AU - Anderson, D Eric
AU - Druey, Kirk M
AU - Mandl, Judith N
AU - Isidor, Bertrand
AU - Ferreira, Carlos R
AU - Freeman, Alexandra F
AU - Ganesan, Sundar
AU - Karsak, Meliha
AU - Mustillo, Peter J
AU - Teo, Juliana
AU - Zolkipli-Cunningham, Zarazuela
AU - Chatron, Nicolas
AU - Lecoquierre, François
AU - Oler, Andrew J
AU - Schmid, Jana Pachlopnik
AU - Kuhns, Douglas B
AU - Xu, Xuehua
AU - Hauck, Fabian
AU - Al-Herz, Waleed
AU - Wagner, Matias
AU - Terhal, Paulien A
AU - Muurinen, Mari
AU - Barlogis, Vincent
AU - Cruz, Phillip
AU - Danielson, Jeffrey
AU - Stewart, Helen
AU - Loid, Petra
AU - Rading, Sebastian
AU - Keren, Boris
AU - Pfundt, Rolph
AU - Zarember, Kol A
AU - Vill, Katharina
AU - Potocki, Lorraine
AU - Olivier, Kenneth N
AU - Lesca, Gaetan
AU - Faivre, Laurence
AU - Wong, Melanie
AU - Puel, Anne
AU - Chou, Janet
AU - Tusseau, Maud
AU - Moutsopoulos, Niki M
AU - Matthews, Helen F
AU - Simons, Cas
AU - Taft, Ryan J
AU - Soldatos, Ariane
AU - Masle-Farquhar, Etienne
AU - Pittaluga, Stefania
AU - Brink, Robert
AU - Fink, Danielle L
AU - Kong, Heidi H
AU - Kabat, Juraj
AU - Kim, Woo Sung
AU - Bierhals, Tatjana
AU - Meguro, Kazuyuki
AU - Hsu, Amy P
AU - Gu, Jingwen
AU - Stoddard, Jennifer
AU - Banos-Pinero, Benito
AU - Slack, Maria
AU - Trivellin, Giampaolo
AU - Mazel, Benoît
AU - Soomann, Maarja
AU - Li, Samuel
AU - Watts, Val J
AU - Stratakis, Constantine A
AU - Rodriguez-Quevedo, Maria F
AU - Bruel, Ange-Line
AU - Lipsanen-Nyman, Marita
AU - Saultier, Paul
AU - Jain, Rashmi
AU - Lehalle, Daphne
AU - Torres, Daniel
AU - Sullivan, Kathleen E
AU - Barbarot, Sébastien
AU - Neu, Axel
AU - Duffourd, Yannis
AU - Similuk, Morgan
AU - McWalter, Kirsty
AU - Blanc, Pierre
AU - Bézieau, Stéphane
AU - Jin, Tian
AU - Geha, Raif S
AU - Casanova, Jean-Laurent
AU - Makitie, Outi M
AU - Kubisch, Christian
AU - Edery, Patrick
AU - Christodoulou, John
AU - Germain, Ronald N
AU - Goodnow, Christopher C
AU - Sakmar, Thomas P
AU - Billadeau, Daniel D
AU - Küry, Sébastien
AU - Katanaev, Vladimir L
AU - Zhang, Yu
AU - Lenardo, Michael J
AU - Su, Helen C
PY - 2024/9/20
Y1 - 2024/9/20
N2 - 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.
AB - 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.
KW - Humans
KW - Germ-Line Mutation
KW - T-Lymphocytes/immunology
KW - Signal Transduction
KW - Receptors, Antigen, T-Cell/metabolism
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Cell Movement
KW - MAP Kinase Signaling System
KW - Cell Proliferation
KW - ras Proteins/metabolism
KW - Phosphatidylinositol 3-Kinases/metabolism
U2 - 10.1126/science.add8947
DO - 10.1126/science.add8947
M3 - SCORING: Journal article
C2 - 39298586
VL - 385
SP - eadd8947
JO - SCIENCE
JF - SCIENCE
SN - 0036-8075
IS - 6715
ER -