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


Editor's Summary

Building Bone
The loss of bone density that afflicts individuals with osteoporosis makes them more vulnerable to bone fractures. One way to counteract decreases in bone density is through exercise, which mechanically stimulates bone tissue and initiates proliferation in bone-forming cells. Alternatively, the signaling pathways that mediate this proliferative response could be therapeutically activated to mimic the effects of mechanical stimulation. Nitric oxide (NO) is a second messenger that is produced in response to mechanical stimulation; it triggers production of cyclic GMP (cGMP) and, consequently, activation of protein kinase G (PKG). Rangaswami et al. delineated a pathway in mechanically stimulated osteoblasts whereby activation of PKGII signaling ultimately leads to a proliferative response. Mechanical stimuli triggered the formation of a complex containing PKGII, the tyrosine kinase Src, the phosphatases SHP-1 and SHP-2, and β3 integrin mechanoreceptors. Activation of Src in this complex led to activation of extracellular signal–regulated kinase (ERK), which in turn elicited changes in gene expression that promote proliferation. Thus, PKG-activating drugs could be used to mimic the anabolic effects of mechanical stimulation on bone in the treatment of osteoporosis. The accompanying Perspective by Bidwell and Pavalko describes other examples of signaling pathways that mediate mechanotransduction in bone cells.

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

Src mediates the mechanical activation of myogenesis by activating TNF{alpha}-converting enzyme.
A. Niu, Y. Wen, H. Liu, M. Zhan, B. Jin, and Y.-P. Li (2013)
J. Cell Sci. 126, 4349-4357
   Abstract »    Full Text »    PDF »
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 »

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