The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors.
The Ras homolog enriched in striatum, Rhes, is the product of a thyroid hormone-regulated gene during brain development. Rhes and the dexamethasone-induced Dexras1 define a novel distinct subfamily of proteins within the Ras family, characterized by an extended variable domain in the carboxyl terminal region. We have carried this study because there is a complete lack of knowledge on Rhes signaling. We show that in PC12 cells, Rhes is targeted to the plasma membrane by farnesylation. We demonstrate that about 30% of the native Rhes protein is bound to GTP and this proportion is unaltered by typical Ras family nucleotide exchange factors. However, Rhes is not transforming in murine fibroblasts. We have also examined the role of Rhes in cell signaling. Rhes does not stimulate the ERK pathway. By contrast, it binds to and activates PI3K. On the other hand, we demonstrate that Rhes impairs the activation of the cAMP/PKA pathway by thyroid-stimulating hormone, and by an activated beta2 adrenergic receptor by a mechanism that suggests uncoupling of the receptor to its cognate heterotrimeric complex. Overall, our results provide the initial insights into the role in signal transduction of this novel Ras family member.
Vargiu
Pierfrancesco
P
Instituto de Investigaciones Biomédicas Alberto Sols. Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain.
De Abajo
Ricardo
R
Garcia-Ranea
Juan Antonio
JA
Valencia
Alfonso
A
Santisteban
Pilar
P
Crespo
Piero
P
Bernal
Juan
J
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D041681:NIH 3T3 Cells; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010802:Phylogeny; D021381:Protein Transport; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000378:metabolism; D015398:Signal Transduction
D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic; D011989:Receptors, Thyrotropin; D006160:Guanosine Triphosphate; D002217:Carbachol; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; C486702:RASD2 protein, human; C442475:Rasd2 protein, rat