Apoptotic signaling through the beta -adrenergic receptor. A new Gs effector pathway.
Stimulation of beta-adrenergic receptor normally results in signaling by the heterotrimeric G protein G(s), leading to the activation of adenylyl cyclase, production of cAMP, and activation of cAMP-dependent protein kinase (PKA). Here we report that cell death of thymocytes can be induced after stimulation of beta-adrenergic receptor, or by addition of exogenous cAMP. Apoptotic cell death in both cases was observed with the appearance of terminal deoxynucleotidyl transferase-mediated UTP end labeling reactivity and the activation of caspase-3 in S49 T cells. Using thymocytes deficient in either Galpha(s) or PKA, we find that engagement of beta-adrenergic receptors initiated a Galpha(s)-dependent, PKA-independent pathway leading to apoptosis. This alternative pathway involves Src family tyrosine kinase Lck. Furthermore, we show that Lck protein kinase activity can be directly stimulated by purified Galpha(s). Our data reveal a new signaling pathway for Galpha(s), distinct from the classical PKA pathway, that accounts for the apoptotic action of beta-adrenergic receptors.
Gu
C
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Graduate Program of Cell Biology and Genetics, Graduate Program of Physiology, Biophysics and Molecular Medicine, and the Department of Physiology, Cornell University Medical College, New York, New York 10021, USA.
Ma
Y C
YC
Benjamin
J
J
Littman
D
D
Chao
M V
MV
Huang
X Y
XY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000172:deficiency / Q000235:genetics; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007545:Isoproterenol / Q000494:pharmacology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D014407:Tumor Cells, Cultured
D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D007545:Isoproterenol