Receptor signaling

GPCRs use Rac and ROS to get to STATs

Science's STKE  04 Feb 2003:
Vol. 2003, Issue 168, pp. tw52-TW52
DOI: 10.1126/stke.2003.168.tw52

The STATs (signal transducers and activators of transcription) are transcription factors that are activated at cytokine receptor complexes through the action of Jak (Janus kinase) cytoplasmic tyrosine kinases. The Jak-STAT pathway can also be activated in response to G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs), but how this occurs has been uncertain because the GPCRs generally do not associate with Jaks. Pelletier et al. present experiments that indicate that in vascular smooth muscle cells activation of receptors for angiotensin II or thrombin stimulates STAT-dependent transcription by a mechanism requiring generation of reactive oxygen species (ROS), which in turn is dependent on activation of Rac, a member of the Rho family of small guanosine triphosphatases (GTPases). They used bacterial toxins or dominant-interfering mutants to show that activity of Rac was necessary for activation of STATs through the GPCRs. Given that ROS have been implicated in activation of the Jak-STAT pathway and that Rac is known to cause generation of ROS through NADPH oxidase, the authors tested for a role of ROS in GPCR-stimulated activation of STATs. Treatment of cells with an inhibitor of NADPH oxidase or with an antioxidant inhibited activation of Jak through the GPCRs. Furthermore, treatment of cells with hydrogen peroxide activated Jaks without a requirement for Rac, and a mutation in Rac that prevents its interaction with the NADPH oxidase complex prevented the overexpressed modified Rac protein from activating Jak2. The effects of toxins also indicated that Rho was required for full activation of the STAT pathway, but in a manner independent of Jaks and tyrosine phosphorylation of STATs. Together the results favor a model in which the GPCRs activate Jaks through a Rac-dependent generation of ROS. How ROS contribute to activation of Jaks is unknown, but the authors note that known redox regulation of tyrosine phosphatases is one plausible mechanism worth consideration.

S. Pelletier, F. Duhamel, P. Coulombe, M. R. Popoff, S. Meloche, Rho family GTPases are required for activation of Jak/STAT signaling by G protein-coupled receptors. Mol. Cell. Biol. 23, 1316-1333 (2003). [Abstract] [Full Text]