The ras-related GTPase rac1 regulates a proliferative pathway selectively utilized by G-protein coupled receptors.
Ras and rac are each members of the superfamily of monomeric GTPases and both function as molecular switches to link cell-surface signals to intracellular responses. Using a novel assay of cellular proliferation called R-SAT (Receptor Selection and Amplification Technology), we examined the roles of ras and rac in mediating the proliferative responses to a variety of cell-surface receptors. Activated, wild-type and dominant-negative mutants of rac and ras were tested for their effects on cellular proliferation either alone or in combination with receptors. Activated rac (rac Q61L, henceforth rac*) and ras (ras G12V, henceforth ras*) each induced strong proliferative responses. Dominant-negative rac (rac T17N, henceforth rac(-)) dramatically suppressed proliferative responses to G-protein coupled receptors (GPCR's) including the m5 muscarinic receptor and the alpha1B adrenergic receptor. In contrast, rac(-) had little or no effect upon responses to the tyrosine kinase receptor TrkC, and only partially suppressed responses to the Janus kinase (JAK/STAT) linked granulocyte macrophage colony stimulating factor (GM-CSF) receptor. Dominant-negative ras (ras T17N, henceforth ras(-)) blocked the proliferative responses to all of the tested receptors. Compared to rac(-) and ras(-), wild-type rac and ras had only modest effects on the tested receptors. Overall these results demonstrate that rac mediates the proliferative effects of G-protein coupled receptors through a pathway that is distinct from the proliferative signaling pathway utilized by tyrosine kinase linked and JAK-linked receptors.
Burstein
E S
ES
ACADIA Pharmaceuticals Inc., San Diego, California 92121, USA.
Hesterberg
D J
DJ
Gutkind
J S
JS
Brann
M R
MR
Currier
E A
EA
Messier
T L
TL
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000235:genetics*; D051379:Mice; D043642:Receptor, Muscarinic M5; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins
D043642:Receptor, Muscarinic M5; D018342:Receptors, Adrenergic, beta-1; D011956:Receptors, Cell Surface; D011976:Receptors, Muscarinic; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins