Science signaling, 2010-12, Vol.3 (153), p.ra91
2010
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Details
- Autor(en) / Beteiligte
- Titel
- Cyclic GMP and protein kinase G control a Src-containing mechanosome in osteoblasts
- Ist Teil von
- Science signaling, 2010-12, Vol.3 (153), p.ra91
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Mechanical stimulation is crucial for bone growth and remodeling, and fluid shear stress promotes anabolic responses in osteoblasts through multiple second messengers, including nitric oxide (NO). NO triggers production of cyclic guanosine 3',5'-monophosphate (cGMP), which in turn activates protein kinase G (PKG). We found that the NO-cGMP-PKG signaling pathway activates Src in mechanically stimulated osteoblasts to initiate a proliferative response. PKGII was necessary for Src activation, a process that also required the interaction of Src with β₃ integrins and dephosphorylation of Src by a complex containing the phosphatases SHP-1 (Src homology 2 domain-containing tyrosine phosphatase 1) and SHP-2. PKGII directly phosphorylated and stimulated SHP-1 activity, and fluid shear stress triggered the recruitment of PKGII, Src, SHP-1, and SHP-2 to a mechanosome containing β₃ integrins. PKGII-null mice showed defective Src and ERK (extracellular signal-regulated kinase) signaling in osteoblasts and decreased ERK-dependent gene expression in bone. Our findings reveal a convergence of NO-cGMP-PKG and integrin signaling and establish a previously unknown mechanism of Src activation. These results support the use of PKG-activating drugs to mimic the anabolic effects of mechanical stimulation of bone in the treatment of osteoporosis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1945-0877eISSN: 1937-9145DOI: 10.1126/scisignal.2001423Titel-ID: cdi_pubmed_primary_21177494
- Format
- –
- Schlagworte
- Analysis of Variance, Animals, Biomechanical Phenomena, Bromodeoxyuridine, Cell Fractionation, Cell Line, Cell Proliferation, Cyclic GMP - metabolism, Cyclic GMP-Dependent Protein Kinases - genetics, Cyclic GMP-Dependent Protein Kinases - metabolism, Extracellular Signal-Regulated MAP Kinases - metabolism, Fluorescent Antibody Technique, Immunoblotting, Immunoprecipitation, Integrin beta Chains - metabolism, Mechanotransduction, Cellular - physiology, Mice, Mice, Knockout, Models, Biological, Nitric Oxide - metabolism, Osteoblasts - metabolism, Osteoblasts - physiology, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism, Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism, Reverse Transcriptase Polymerase Chain Reaction, Second Messenger Systems - physiology, src-Family Kinases - metabolism, Stress, Mechanical