Src Kinase Regulates the Activation of a Novel FGD-1-related Cdc42 Guanine Nucleotide Exchange Factor in the Signaling Pathway from the Endothelin A Receptor to JNK

Yuki Miyamoto,Junji Yamauchi,Hiroshi Itoh

doi:10.1074/jbc.m301559200

Abstract

Small GTPases act as binary switches by cycling between an inactive (GDP-bound) and an active (GTP-bound) state. Upon stimulation with extracellular signals, guanine-nucleotide exchange factors (GEFs) stimulate the exchange of GDP to GTP to shift toward the active forms of small GTPases, recognizing the downstream targets. Here we show that KIAA0793, containing substantial sequence homology with the catalytic Dbl homology domain of the faciogenital dysplasia gene product (FGD1), is a specific GEF for Cdc42. We, therefore, tentatively named it FRG (FGD1-related Cdc42-GEF). Src kinase directly phosphorylates and activates FRG, as Vav family GEFs. Additionally, FRG is involved in the signaling pathway from the endothelin A receptor to c-Jun N-terminal kinase, resulting in the inhibition of cell motility. These results suggest that FRG is a member of Cdc42-GEF and plays an important role in the signaling pathway downstream of G protein-coupled receptors.

Highlights

Small GTPases act as binary switches by cycling between an inactive (GDP-bound) and an active (GTPbound) state
We previously showed that endothelin, a ligand of G protein-coupled receptors (GPCRs), activates Jun N-terminal kinase (JNK) via the signaling pathway dependent upon Src kinase and Rho family GTPases Rac1 and Cdc42 [33]
Our results indicate that FRG is a novel member of Cdc42-guanine-nucleotide exchange factors (GEFs) and may act as a direct regulator linking the Src kinase and Rho family GTPases in the chemorepellant GPCR-JNK-signaling pathway

Summary

Introduction

Small GTPases act as binary switches by cycling between an inactive (GDP-bound) and an active (GTPbound) state. Src kinase directly phosphorylates and activates FRG, as Vav family GEFs. FRG is involved in the signaling pathway from the endothelin A receptor to c-Jun N-terminal kinase, resulting in the inhibition of cell motility. We previously showed that endothelin, a ligand of GPCRs, activates JNK via the signaling pathway dependent upon Src kinase and Rho family GTPases Rac1 and Cdc42 [33].

Results

Conclusion