LPA2 receptor mediates mitogenic signals in human colon cancer cells.
Lysophosphatidic acid (LPA) is a mediator of multiple cellular responses. LPA mediates its effects predominantly through the G protein-coupled receptors LPA1, LPA2, and LPA3. In the present work, we studied LPA2-mediated signaling using human colon cancer cell lines, which predominantly express LPA2. LPA2 activated Akt and Erk1/2 in response to LPA. LPA mediated Akt activation was inhibited by pertussis toxin (PTX), whereas Erk1/2 activation was completely inhibited by a blocker of phospholipase Cbeta, U-73122. LPA also induced interleukin-8 (IL-8) synthesis in the colon cancer cells by primarily activating LPA2 receptor. We also found that LPA2 interacts with Na+/H+ exchanger regulatory factor 2 (NHERF2). Activation of Akt and Erk1/2 was significantly attenuated by silencing of NHERF2 expression by RNA interference, suggesting a pivotal role of NHERF2 in LPA2-mediated signaling. We found that expression of LPA2 was elevated, whereas expression of LPA1 downregulated in several types of cancers, including ovarian and colon cancer. We conclude that LPA2 is the major LPA receptor in colon cancer cells and cellular signals by LPA2 are largely mediated through its ability to interact with NHERF2.
Yun
C Chris
CC
Department of Medicine, Division of Digestive Diseases, Emory University School of Medicine, Whitehead Bldg., Suite 201, 615 Michael St., Atlanta, Georgia 30322, USA. ccyun@emory.edu
Sun
Hong
H
Wang
Dongsheng
D
Rusovici
Raluca
R
Castleberry
Amanda
A
Hall
Randy A
RA
Shim
Hyunsuk
H
D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D004789:Enzyme Activation; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008938:Mitosis; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers
D003598:Cytoskeletal Proteins; D016209:Interleukin-8; D008246:Lysophospholipids; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; C032881:lysophosphatidic acid