RRC ID 61865
Author Fujita T, Meguro T, Fukuyama R, Nakamuta H, Koida M.
Title New signaling pathway for parathyroid hormone and cyclic AMP action on extracellular-regulated kinase and cell proliferation in bone cells. Checkpoint of modulation by cyclic AMP.
Journal J Biol Chem
Abstract cAMP signaling, activated by extracellular stimuli such as parathyroid hormone, has cell type-specific effects important for cellular proliferation and differentiation in bone cells. Recent evidence of a second enzyme target for cAMP suggests divergent effects on extracellular-regulated kinase (ERK) activity depending on Epac/Rap1/B-Raf signaling. We investigated the molecular mechanism of the dual functionality of cAMP on cell proliferation in clonal bone cell types. MC3T3-E1 and ATDC5, but not MG63, express a 95-kDa isoform of B-Raf. cAMP stimulated Ras-independent and Rap1-dependent ERK phosphorylation and cell proliferation in B-Raf-expressing cells, but inhibited growth in B-Raf-lacking cells. The mitogenic action of cAMP was blocked by the ERK pathway inhibitor PD98059. In B-Raf-transduced MG63 cells, cAMP stimulated ERK activation and cell proliferation. Thus, B-Raf is the dominant molecular switch that permits differential cAMP-dependent regulation of ERK with important implications for cell proliferation in bone cells. These findings might explain the dual functionality of parathyroid hormone on osteoblastic cell proliferation.
Volume 277(25)
Pages 22191-200
Published 2002-6-21
DOI 10.1074/jbc.M110364200
PII S0021-9258(19)66802-X
PMID 11956184
MeSH 3T3 Cells Animals Blotting, Northern Bone and Bones / cytology* Cell Division Cell Line Cyclic AMP / metabolism* Dose-Response Relationship, Drug Enzyme Inhibitors / pharmacology Genes, Dominant Humans Immunoblotting Mice Mice, Inbred C3H Mitogen-Activated Protein Kinases / metabolism* PC12 Cells Parathyroid Hormone / metabolism* Phosphorylation Protein Isoforms RNA, Messenger / metabolism Rats Signal Transduction* Skull / metabolism Time Factors Tissue Distribution Tumor Cells, Cultured rap1 GTP-Binding Proteins / metabolism
IF 4.238
Human and Animal Cells ATDC5(RCB0565) MC3T3-E1(RCB1126) 10T1/2(RCB0247) C2C12(RCB0987)