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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

Harvard

Ham, H, Jing, H, Lamborn, IT, Kober, MM, Koval, A, Berchiche, YA, Anderson, DE, Druey, KM, Mandl, JN, Isidor, B, Ferreira, CR, Freeman, AF, Ganesan, S, Karsak, M, Mustillo, PJ, Teo, J, Zolkipli-Cunningham, Z, Chatron, N, Lecoquierre, F, Oler, AJ, Schmid, JP, Kuhns, DB, Xu, X, Hauck, F, Al-Herz, W, Wagner, M, Terhal, PA, Muurinen, M, Barlogis, V, Cruz, P, Danielson, J, Stewart, H, Loid, P, Rading, S, Keren, B, Pfundt, R, Zarember, KA, Vill, K, Potocki, L, Olivier, KN, Lesca, G, Faivre, L, Wong, M, Puel, A, Chou, J, Tusseau, M, Moutsopoulos, NM, Matthews, HF, Simons, C, Taft, RJ, Soldatos, A, Masle-Farquhar, E, Pittaluga, S, Brink, R, Fink, DL, Kong, HH, Kabat, J, Kim, WS, Bierhals, T, Meguro, K, Hsu, AP, Gu, J, Stoddard, J, Banos-Pinero, B, Slack, M, Trivellin, G, Mazel, B, Soomann, M, Li, S, Watts, VJ, Stratakis, CA, Rodriguez-Quevedo, MF, Bruel, A-L, Lipsanen-Nyman, M, Saultier, P, Jain, R, Lehalle, D, Torres, D, Sullivan, KE, Barbarot, S, Neu, A, Duffourd, Y, Similuk, M, McWalter, K, Blanc, P, Bézieau, S, Jin, T, Geha, RS, Casanova, J-L, Makitie, OM, Kubisch, C, Edery, P, Christodoulou, J, Germain, RN, Goodnow, CC, Sakmar, TP, Billadeau, DD, Küry, S, Katanaev, VL, Zhang, Y, Lenardo, MJ & Su, HC 2024, 'Germline mutations in a G protein identify signaling cross-talk in T cells', SCIENCE, vol. 385, no. 6715, pp. eadd8947. https://doi.org/10.1126/science.add8947

APA

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., ... Su, H. C. (2024). Germline mutations in a G protein identify signaling cross-talk in T cells. SCIENCE, 385(6715), eadd8947. https://doi.org/10.1126/science.add8947

Vancouver

Ham H, Jing H, Lamborn IT, Kober MM, Koval A, Berchiche YA et al. Germline mutations in a G protein identify signaling cross-talk in T cells. SCIENCE. 2024 Sep 20;385(6715):eadd8947. https://doi.org/10.1126/science.add8947

Bibtex

@article{602b492ac8ef4eb29b74e13a3ba12a63,
title = "Germline mutations in a G protein identify signaling cross-talk in T cells",
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 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.",
keywords = "Humans, Germ-Line Mutation, T-Lymphocytes/immunology, Signal Transduction, Receptors, Antigen, T-Cell/metabolism, Proto-Oncogene Proteins c-akt/metabolism, Cell Movement, MAP Kinase Signaling System, Cell Proliferation, ras Proteins/metabolism, Phosphatidylinositol 3-Kinases/metabolism",
author = "Hyoungjun Ham and Huie Jing and Lamborn, {Ian T} and Kober, {Megan M} and Alexey Koval and Berchiche, {Yamina A} and Anderson, {D Eric} and Druey, {Kirk M} and Mandl, {Judith N} and Bertrand Isidor and Ferreira, {Carlos R} and Freeman, {Alexandra F} and Sundar Ganesan and Meliha Karsak and Mustillo, {Peter J} and Juliana Teo and Zarazuela Zolkipli-Cunningham and Nicolas Chatron and Fran{\c c}ois Lecoquierre and Oler, {Andrew J} and Schmid, {Jana Pachlopnik} and Kuhns, {Douglas B} and Xuehua Xu and Fabian Hauck and Waleed Al-Herz and Matias Wagner and Terhal, {Paulien A} and Mari Muurinen and Vincent Barlogis and Phillip Cruz and Jeffrey Danielson and Helen Stewart and Petra Loid and Sebastian Rading and Boris Keren and Rolph Pfundt and Zarember, {Kol A} and Katharina Vill and Lorraine Potocki and Olivier, {Kenneth N} and Gaetan Lesca and Laurence Faivre and Melanie Wong and Anne Puel and Janet Chou and Maud Tusseau and Moutsopoulos, {Niki M} and Matthews, {Helen F} and Cas Simons and Taft, {Ryan J} and Ariane Soldatos and Etienne Masle-Farquhar and Stefania Pittaluga and Robert Brink and Fink, {Danielle L} and Kong, {Heidi H} and Juraj Kabat and Kim, {Woo Sung} and Tatjana Bierhals and Kazuyuki Meguro and Hsu, {Amy P} and Jingwen Gu and Jennifer Stoddard and Benito Banos-Pinero and Maria Slack and Giampaolo Trivellin and Beno{\^i}t Mazel and Maarja Soomann and Samuel Li and Watts, {Val J} and Stratakis, {Constantine A} and Rodriguez-Quevedo, {Maria F} and Ange-Line Bruel and Marita Lipsanen-Nyman and Paul Saultier and Rashmi Jain and Daphne Lehalle and Daniel Torres and Sullivan, {Kathleen E} and S{\'e}bastien Barbarot and Axel Neu and Yannis Duffourd and Morgan Similuk and Kirsty McWalter and Pierre Blanc and St{\'e}phane B{\'e}zieau and Tian Jin and Geha, {Raif S} and Jean-Laurent Casanova and Makitie, {Outi M} and Christian Kubisch and Patrick Edery and John Christodoulou and Germain, {Ronald N} and Goodnow, {Christopher C} and Sakmar, {Thomas P} and Billadeau, {Daniel D} and S{\'e}bastien K{\"u}ry and Katanaev, {Vladimir L} and Yu Zhang and Lenardo, {Michael J} and Su, {Helen C}",
year = "2024",
month = sep,
day = "20",
doi = "10.1126/science.add8947",
language = "English",
volume = "385",
pages = "eadd8947",
journal = "SCIENCE",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6715",

}

RIS

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 -