Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor.
We previously described two mammalian secreted proteins, prokineticin 1 and prokineticin 2, that potently contract gastrointestinal smooth muscle. Prokineticin 1 has also been shown to promote angiogenesis by stimulating proliferation, migration, and fenestration of endocrine organ-derived endothelial cells. Here we report the cloning and characterization of two closely related G protein-coupled receptors as receptors for prokineticins. Expression of prokineticin receptors in heterologous systems shows that these receptors bind to and are activated by nanomolar concentrations of recombinant prokineticins. Activation of prokineticin receptors leads to mobilization of calcium, stimulation of phosphoinositide turnover, and activation of p44/p42 MAPK signaling pathways that are consistent with the effects of prokineticins on smooth muscle contraction and angiogenesis. mRNA expression analysis reveals that prokineticin receptors are expressed in gastrointestinal organs, endocrine glands, and other tissues.
Lin
Daniel Chi-Hong
DC
Tularik Inc., South San Francisco, California 94080, USA.
Bullock
Clayton M
CM
Ehlert
Frederick J
FJ
Chen
Jin-Long
JL
Tian
Hui
H
Zhou
Qun-Yong
QY
D000331:Aequorin / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004702:Endocrine Glands / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000737:chemistry / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008222:Lymphokines / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009479:Neuropeptides; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D042442:Vascular Endothelial Growth Factors
D018076:DNA, Complementary; D016228:Endothelial Growth Factors; D005768:Gastrointestinal Hormones; D008024:Ligands; D008222:Lymphokines; D009479:Neuropeptides; C467610:PROK1 protein, human; C423608:PROK2 protein, human; C486586:Prok2 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D042442:Vascular Endothelial Growth Factors; D000331:Aequorin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D002118:Calcium