RRC ID 41494
Author Suzawa M, Tamura Y, Fukumoto S, Miyazono K, Fujita T, Kato S, Takeuchi Y.
Title Stimulation of Smad1 transcriptional activity by Ras-extracellular signal-regulated kinase pathway: a possible mechanism for collagen-dependent osteoblastic differentiation.
Journal J Bone Miner Res
Abstract Signals from bone morphogenetic protein receptors (BMPRs) and cell adhesion to type I collagen are both important for osteoblastic differentiation and functions. BMP signals are mediated mostly by Smad and collagen signals are transduced by integrins to activate focal adhesion kinase (FAK) and its downstream molecules. This study was undertaken to clarify how extracellular matrix collagen signals converge with BMP actions. We show that integrin activation by collagen was involved in BMP signals because disruption of either collagen synthesis or collagen-alpha2beta1-integrin binding inhibited the stimulatory effect of BMP-2 on osteoblastic MC3T3-E1 cells. Downstream signals of collagen-integrin might be FAK-Ras-extracellular signal-regulated kinase (ERK) in osteoblastic cells. We further show that Ras-ERK signals enhanced the transcriptional activity of Smad1 in response to BMP in these cells transiently transfected with expression plasmids for a constitutively active mutant RasV12, a dominant negative mutant RasN17, and an ERK phosphatase CL100. Ras-ERK signals did not augment the transcriptional activity of Smad3 in response to transforming growth factor beta (TGF-beta) receptor activation but that of Smad1 in response to BMPR activation as examined in COS-1 cells. These observations suggest that the Ras-ERK pathway downstream of integrin-FAK is involved in Smad1 signals activated by BMP and provide a possible mechanism for cooperation between intracellular signals activated by integrin and BMPRs in osteoblastic cells.
Volume 17(2)
Pages 240-8
Published 2002-2-1
DOI 10.1359/jbmr.2002.17.2.240
PMID 11811554
MeSH Activin Receptors, Type I / genetics Activin Receptors, Type I / metabolism Animals Bone Morphogenetic Protein 2 Bone Morphogenetic Proteins / metabolism* Bone Morphogenetic Proteins / pharmacology Cell Differentiation Cells, Cultured Collagen / metabolism* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Enzyme Inhibitors / pharmacology Epidermal Growth Factor / pharmacology Flavonoids / pharmacology Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases Humans Integrins / metabolism Mice Mitogen-Activated Protein Kinases / antagonists & inhibitors Mitogen-Activated Protein Kinases / drug effects Mitogen-Activated Protein Kinases / metabolism* Osteoblasts / cytology Osteoblasts / drug effects Osteoblasts / metabolism* Protein-Serine-Threonine Kinases Protein-Tyrosine Kinases / genetics Protein-Tyrosine Kinases / metabolism Receptor, Transforming Growth Factor-beta Type I Receptors, Collagen Receptors, Transforming Growth Factor beta / genetics Receptors, Transforming Growth Factor beta / metabolism Signal Transduction Smad Proteins Smad1 Protein Trans-Activators / genetics Trans-Activators / metabolism* Transcription, Genetic Transforming Growth Factor beta* ras Proteins / metabolism*
IF 5.711
Times Cited 74
Human and Animal Cells