Subtype-specific differential regulation of Rho family G proteins and cell migration by the Edg family sphingosine-1-phosphate receptors.
One of the striking activities of the Edg family sphingosine-1-phosphate (S1P) receptors includes receptor isotype-specific, bimodal regulatory activity on cell migration. While Edg1 and Edg3 act as typical chemotactic receptors, Edg5 uniquely acts as a chemorepellant receptor. Consistent with this, Edg1 and Edg3, and Edg5 regulate the activity of the Rho family GTPase Rac positively and negatively, respectively. Thus, Edg isotype-specific, differential regulatory activities on Rac seem to be important as mechanisms underlying the bimodal regulation of cell migration by S1P. Edg5-mediated Rac inhibition involves stimulation of Rac-GTPase-activating protein (GAP) activity, rather than inhibition of Rac-guanine nucleotide exchange factor (GEF) activity. Many cell types including vascular smooth muscle and endothelial cells express more than a single S1P receptor isotype. In these cells, it appears that an integration of the Edg isotype-selective, positive and negative signals on cellular Rac activity is a critical determinant for eventual direction of regulation on cell motility by S1P. Physiological and pathological roles for the repulsive activity of Edg5 receptor remain to be clarified.
Takuwa
Yoh
Y
Department of Physiology, Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan. ytakuwa@med.kanazawa-u.ac.jp
D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000502:physiology; D008246:Lysophospholipids; D000072000:NF-KappaB Inhibitor alpha; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000502:physiology*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins; D008246:Lysophospholipids; C000606204:NFKBIA protein, human; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D000072000:NF-KappaB Inhibitor alpha; C060506:sphingosine 1-phosphate; D020741:rho GTP-Binding Proteins; D013110:Sphingosine