Thrombin and lysophosphatidic acid receptors utilize distinct rhoGEFs in prostate cancer cells.
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.
Wang
Qin
Q
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Liu
Min
M
Kozasa
Tohru
T
Rothstein
Jeffrey D
JD
Sternweis
Paul C
PC
Neubig
Richard R
RR
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
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