Lysophosphatidic acid stimulates CREB through mitogen- and stress-activated protein kinase-1.
Lysophosphatidic acid (LPA) is a growth factor-like phospholipid that elicits a variety of cellular responses in numerous cell types, including neurons, immune cells, and fibroblasts. In this report, we investigated the possibility that LPA activates the transcription factor cAMP response element-binding protein, CREB, in Rat-2 fibroblast cells. CREB is activated in many cells downstream of signaling events, such as growth factor and neurotrophin stimulation. We found that LPA rapidly stimulated phosphorylation of CREB at Ser133 in a time- and dose-dependent manner, as revealed by immunoblot analysis with a phospho-specific antibody recognizing CREB on Ser133. LPA-induced phosphorylation of CREB was dependent on the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK). Inhibition of ERK1/2 with PD98059 and of p38 MAPK with SB203580 efficiently blocked LPA-mediated phosphorylation of CREB. The LPA-induced CREB phosphorylation was abolished by H89, an inhibitor of mitogen- and stress-activated protein kinase-1 (MSK1). Together, these data suggest that LPA stimulates nuclear transcription factor CREB via mitogen-activated protein kinase signaling components, ERK1/2, p38 MAPK, and MSK1 in Rat-2 fibroblast cells.
Lee
Chang-Wook
CW
Department of Pharmacology, College of Medicine, Institute of Natural Medicine, Hallym University, Chunchon, Kangwon-do 200-702, Republic of Korea.
Nam
Ju-Suk
JS
Park
Yoon-Kyung
YK
Choi
Ho-Kyew
HK
Lee
Joo-Hyun
JH
Kim
Nam-Ho
NH
Cho
Jaeyoung
J
Song
Dong-Keun
DK
Suh
Hong-Won
HW
Lee
Jongho
J
Kim
Yung-Hi
YH
Huh
Sung-Oh
SO
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007700:Kinetics; D008246:Lysophospholipids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D051381:Rats; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism* / Q000502:physiology; D012694:Serine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D017362:Cyclic AMP Response Element-Binding Protein; D008246:Lysophospholipids; D012694:Serine; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases