Small GTPase Rac Links Receptors to cGMP Formation

Abstract

The second messenger guanosine 3′,5′-monophosphate (cGMP) controls a broad range of cellular functions, many of which are regulated through the cGMP-dependent protein kinase. Cyclic GMP is synthesized by guanylyl cyclases (GCs) that catalyze their formation from guanosine triphosphate. A study by Guo et al . provides insight into the upstream regulation of the GCs. Unlike the adenyl cyclases, which are well known as targets of GPCRs [heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors], transmembrane guanylyl cyclases are thought to act as receptors themselves, although not all have identified ligands. Guo et al . explored how intracellular signals can also regulate the transmembrane guanylyl cyclase GC-E and observed that transient overexpression of the small GTPase Rac1 led to activation of GC-E. Activation of the platelet-derived growth factor receptor (PDGFR) also stimulated formation of cGMP, and this was inhibited when the authors used a dominant-negative form of Rac1 to inhibit activity of endogenous Rac1. The authors tested known targets of Rac1 to explore how Rac1 might be coupled to activation of GC-E. PAK (p21-activated protein kinase) is one such target, and it could substitute for Rac1 in activating formation of cGMP; expression of the autoinhibitory domain of PAK also inhibited the effect of constitutively active Rac1 to stimulate GC-E activity. The authors used in vitro and in vivo studies with purified proteins and protein fragments to show that PAK directly interacts with and stimulates GC-E. This activation required the kinase activity of PAK--but apparently only for autophosphorylation, because GC-E was not phosphorylated by PAK. This new pathway from receptor tyrosine kinase to cGMP was shown to be physiologically important in the control of cell migration. Depletion of GC-A in mouse embryo fibroblasts with small interfering RNA (siRNA) reduced the effect of PDGF on accumulation of cGMP and inhibited PDGF-dependent cell migration and formation of lamellipodia. Settleman discusses the work in a commentary and emphasizes some of the intriguing questions raised by the work, such as why Cdc42, another small GTPase that also activates PAK, fails to activate GC-E. D. Guo, Y.-C. Tan, D. Wang, K. S. Madhusoodanan, Y. Zheng, T. Maack, J. J. Zhang, X.-Y. Huang, A Rac-cGMP signaling pathway. Cell 128 , 341-355 (2007). [Online Journal] J. Settleman, PAK-in’ up cGMP for the move. Cell 128 , 237-238 (2007). [Online Journal]