title: Thrombin and lysophosphatidic acid receptors utilize distinct rhoGEFs in prostate cancer cells.
abstract: Thrombin and lysophosphatidic acid (LPA) receptors play important roles in vascular biology, development, and cancer. These receptors activate rho via G(12/13) family heterotrimeric G proteins, which are known to directly activate three distinct rho guanine nucleotide exchange factors (rhoGEFs) that contain a regulator of G protein signaling (RGS) domain (RGS-rhoGEFs). However, it is not known which, if any, of these RGS-rhoGEFs (LARG (leukemia-associated rhoGEF), p115rhoGEF, or PDZrhoGEF) plays a role in G protein-coupled receptor-stimulated rho signaling. Using oligonucleotide small interfering RNAs that suppress specific RGS-rhoGEF expression, we show that thrombin receptor stimulation of rho is primarily mediated by LARG in HEK293T and PC-3 prostate cancer cell lines. In contrast, the LPA-stimulated rho response in PC-3 cells is dependent on PDZrhoGEF expression. Suppression of p115rhoGEF had no effect. Thus different rhoGEFs (LARG and PDZrhoGEF) mediate downstream rho signaling by the thrombin and LPA receptors.
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Tohru
authors.initials: T
authors.lastname: Kozasa
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: Paul C
authors.initials: PC
authors.lastname: Sternweis
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
mesh_terms: D045744:Cell Line, Tumor; D048429:Cell Size; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid; D018179:Receptors, Thrombin / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000502:physiology; D013917:Thrombin / Q000378:metabolism
chemical_list: C577234:ARHGEF11 protein, human; C577222:ARHGEF12 protein, human; D020662:Guanine Nucleotide Exchange Factors; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D017470:Receptors, Glutamate; D049368:Receptors, Lysophosphatidic Acid; D018179:Receptors, Thrombin; D064067:Rho Guanine Nucleotide Exchange Factors; D013917:Thrombin; C032881:lysophosphatidic acid