Rho GTPase-dependent transformation by G protein-coupled receptors.
G protein coupled receptors (GPCRs) constitute the largest family of cell surface receptors, with more than 1000 members, and are responsible for converting a diverse array of extracellular stimuli into intracellular signaling events. Most members of the family have defined roles in intermediary metabolism and generally perform these functions in well-differentiated cells. However, there is an increasing awareness that some GPCRs can also regulate proliferative signaling pathways and that chronic stimulation or mutational activation of receptors can lead to oncogenic transformation. Activating mutations in GPCRs are associated with several types of human tumors and some receptors exhibit potent oncogenic activity due to agonist overexpression. Additionally, expression screening analyses for novel oncogenes identified GPCRs whose expression causes the oncogenic transformation of NIH3T3 mouse fibroblasts. These include Mas, G2A, and the PAR-1 thrombin receptor. In this review we summarize the signaling and transforming properties of these GPCR oncoproteins. What has emerged from these studies is the delineation of a GTPase cascade where transforming GPCRs cause aberrant growth regulation via activation of Rho family small GTPases.
Whitehead
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Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, Newark, New Jersey, NJ 07103-2714, USA.
Zohn
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Der
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CJ
D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D008954:Models, Biological; D009857:Oncogenes; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D018179:Receptors, Thrombin; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; C115270:G2A receptor; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D018179:Receptors, Thrombin; D020962:Heterotrimeric GTP-Binding Proteins; D020741:rho GTP-Binding Proteins