[Show abstract][Hide abstract] ABSTRACT: The small GTPase Rac and the second messenger cGMP (guanosine 3',5'-cyclic monophosphate) are critical regulators of diverse cell functions. When activated by extracellular signals via membrane signaling receptors, Rac executes its functions through engaging downstream effectors such as p21-activated kinase (PAK), a serine/threonine protein kinase. However, the molecular mechanism by which membrane signaling receptors regulate cGMP levels is not known. Here we have uncovered a signaling pathway linking Rac to the increase of cellular cGMP. We show that Rac uses PAK to directly activate transmembrane guanylyl cyclases (GCs), leading to increased cellular cGMP levels. This Rac/PAK/GC/cGMP pathway is involved in platelet-derived growth factor-induced fibroblast cell migration and lamellipodium formation. Our findings connect two important regulators of cellular physiological functions and provide a general mechanism for diverse receptors to modulate physiological responses through elevating cellular cGMP levels.
[Show abstract][Hide abstract] ABSTRACT: Growth factors induce massive actin cytoskeletal remodeling in cells. These reorganization events underlie various cellular
responses such as cell migration and morphological changes. One major form of actin reorganization is the formation and disassembly
of dorsal ruffles (also named waves, dorsal rings, or circular ruffles). Dorsal ruffles are involved in physiological functions
including cell migration, invasion, macropinocytosis, plasma membrane recycling, and others. Growth factors initiate rapid
formation (within 5 min) of circular membrane ruffles, and these ruffles move along the dorsal side of the cells, constrict,
close, and eventually disassemble (∼20 min). Considerable attention has been devoted to the mechanism by which growth factors
induce the formation of dorsal ruffles. However, little is known of the mechanism by which these ruffles are disassembled.
Here we have shown that G proteins G12 and G13 control the rate of disassembly of dorsal ruffles. In Gα12-/-Gα13-/- fibroblast cells, dorsal ruffles induced by growth factor treatment remain visible substantially longer (∼60 min) than in
wild-type cells, whereas the rate of formation of these ruffles was the same with or without Gα12 and Gα13. Thus, Gα12/Gα13 critically regulate dorsal ruffle turnover.
Preview · Article · Nov 2006 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Heterotrimeric G proteins are critical cellular signal transducers. They are known to directly relay signals from seven-transmembrane G protein-coupled receptors (GPCRs) to downstream effectors. On the other hand, receptor tyrosine kinases (RTKs), a different family of membrane receptors, signal through docking sites in their carboxy-terminal tails created by autophosphorylated tyrosine residues. Here we show that a heterotrimeric G protein, G alpha(13), is essential for RTK-induced migration of mouse fibroblast and endothelial cells. G alpha(13) activity in cell migration is retained in a C-terminal mutant that is defective in GPCR coupling, suggesting that the migration function is independent of GPCR signaling. Thus, G alpha(13) appears to be a critical signal transducer for RTKs as well as GPCRs. This broader role of G alpha(13) in cell migration initiated by two types of receptors could provide a molecular basis for the vascular system defects exhibited by G alpha(13) knockout mice.