Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Sci. Signal., 21 December 2010
Vol. 3, Issue 153, p. ra91
[DOI: 10.1126/scisignal.2001423]

RESEARCH ARTICLES

Cyclic GMP and Protein Kinase G Control a Src-Containing Mechanosome in Osteoblasts

Hema Rangaswami1, Raphaela Schwappacher1, Nisha Marathe1, Shunhui Zhuang1, Darren E. Casteel1, Bodo Haas2, Yong Chen2, Alexander Pfeifer2, Hisashi Kato1, Sanford Shattil1, Gerry R. Boss1, and Renate B. Pilz1*

1 Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2 Institute for Pharmacology and Toxicology and Biomedical Center, University of Bonn, 53105 Bonn, Germany.

Abstract: 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.

* To whom correspondence should be addressed. E-mail: rpilz{at}ucsd.edu

Citation: H. Rangaswami, R. Schwappacher, N. Marathe, S. Zhuang, D. E. Casteel, B. Haas, Y. Chen, A. Pfeifer, H. Kato, S. Shattil, G. R. Boss, R. B. Pilz, Cyclic GMP and Protein Kinase G Control a Src-Containing Mechanosome in Osteoblasts. Sci. Signal. 3, ra91 (2010).

Read the Full Text

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
cGMP-dependent protein kinase I{beta} regulates breast cancer cell migration and invasion via interaction with the actin/myosin-associated protein caldesmon.
R. Schwappacher, H. Rangaswami, J. Su-Yuo, A. Hassad, R. Spitler, and D. E. Casteel (2013)
J. Cell Sci. 126, 1626-1636
   Abstract »    Full Text »    PDF »
Calcium-permeable {alpha}-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors Trigger Neuronal Nitric-oxide Synthase Activation to Promote Nerve Cell Death in an Src Kinase-dependent Fashion.
R. Socodato, F. N. Santiago, C. C. Portugal, A. F. Domingues, A. R. Santiago, J. B. Relvas, A. F. Ambrosio, and R. Paes-de-Carvalho (2012)
J. Biol. Chem. 287, 38680-38694
   Abstract »    Full Text »    PDF »
Rho Isoform-specific Interaction with IQGAP1 Promotes Breast Cancer Cell Proliferation and Migration.
D. E. Casteel, S. Turner, R. Schwappacher, H. Rangaswami, J. Su-Yuo, S. Zhuang, G. R. Boss, and R. B. Pilz (2012)
J. Biol. Chem. 287, 38367-38378
   Abstract »    Full Text »    PDF »
A Role for cGMP in Inducible Nitric-oxide Synthase (iNOS)-induced Tumor Necrosis Factor (TNF) {alpha}-converting Enzyme (TACE/ADAM17) Activation, Translocation, and TNF Receptor 1 (TNFR1) Shedding in Hepatocytes.
R. S. Chanthaphavong, P. A. Loughran, T. Y. S. Lee, M. J. Scott, and T. R. Billiar (2012)
J. Biol. Chem. 287, 35887-35898
   Abstract »    Full Text »    PDF »
Protein Kinase G and Focal Adhesion Kinase Converge on Src/Akt/{beta}-Catenin Signaling Module in Osteoblast Mechanotransduction.
H. Rangaswami, R. Schwappacher, T. Tran, G. C. Chan, S. Zhuang, G. R. Boss, and R. B. Pilz (2012)
J. Biol. Chem. 287, 21509-21519
   Abstract »    Full Text »    PDF »
Pro-survival Effects of 17{beta}-Estradiol on Osteocytes Are Mediated by Nitric Oxide/cGMP via Differential Actions of cGMP-dependent Protein Kinases I and II.
N. Marathe, H. Rangaswami, S. Zhuang, G. R. Boss, and R. B. Pilz (2012)
J. Biol. Chem. 287, 978-988
   Abstract »    Full Text »    PDF »
Mechanosomes Carry a Loaded Message.
J. P. Bidwell and F. M. Pavalko (2010)
Science Signaling 3, pe51
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882