Role of G beta-subunit in angiotensin II-type 1 receptor signaling.
The G-protein-coupled angiotensin II-type 1 (AT1) receptor activates the mitogen-activated protein (MAP) kinase cascade and the Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) cascade via tyrosine phosphorylation. Recent observations indicated that the G beta-subunit of heterotrimeric G-proteins interacts with tyrosine phosphorylated proteins. We investigated whether angiotensin II (ANG II) activates MAP-kinases and JAK/STAT cascades via the G beta-subunit. In rat aortic smooth muscle (RASM) cells we found phosphorylated proteins associated with the G beta-subunit SHC (Sequence Homology of Collagen) and JAK2. We demonstrate that JAK2 activity increased upon G beta-binding. The activity of pp60(c-src) kinase also increased, but upon activation pp60(c-src) dissociates from the G beta-complex. Immunoprecipitations revealed that SHC forms a complex with JAK2. Blockade of JAK2 with AG490 abolished this complex formation; therefore, JAK2 may be the kinase responsible for SHC phosphorylation. Thus, the G beta-subunit may play a pivotal role in AT1-receptor signaling by connecting signaling cascades leading to cell growth and differentiation.
Luchtefeld
M
M
Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
Drexler
H
H
Schieffer
B
B
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D053614:Janus Kinase 2; D046911:Macromolecular Substances; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D015398:Signal Transduction
D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D016392:Proto-Oncogene Proteins pp60(c-src); D020962:Heterotrimeric GTP-Binding Proteins