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Review
. 2012:88:55-72.
doi: 10.1016/B978-0-12-394622-5.00003-1.

Noncanonical Hedgehog signaling

Donna Brennan  1 , Xiaole Chen, Lan Cheng, My Mahoney, Natalia A Riobo
Affiliations
Review

Noncanonical Hedgehog signaling

Donna Brennan et al. Vitam Horm. 2012.

Abstract

The notion of noncanonical hedgehog (Hh) signaling in mammals has started to receive support from numerous observations. By noncanonical, we refer to all those cellular and tissue responses to any of the Hh isoforms that are independent of transcriptional changes mediated by the Gli family of transcription factors. In this chapter, we discuss the most recent findings that suggest that Patched1 can regulate cell proliferation and apoptosis independently of Smoothened (Smo) and Gli and the reports that Smo modulates actin cytoskeleton-dependent processes such as fibroblast migration, endothelial cell tubulogenesis, axonal extension, and neurite formation by diverse mechanisms that exclude any involvement of Gli-dependent transcription. We also acknowledge the existence of less stronger evidence of noncanonical signaling in Drosophila.

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Figures

Figure 3.1
Figure 3.1
Schematic representation of the two types of noncanonical Hh signaling. Type I requires only binding of an Hh isoform to Ptc1 and is mediated by novel functions of Ptc1 unrelated to Smo repression, and it is by definition insensitive to Smo modulators. Type II is dependent on Smo and in some cases it has been shown to rely on signaling through Gi proteins, and it is both mimicked by Smo agonists and inhibited by Smo antagonists.
Figure 3.2
Figure 3.2
Apoptosis was assessed by caspase-3 activity measurement of serum starved HUVECs in the absence (control) or in the presence of 2.5μg/ml Shh (Shh), 0.5μM Smo agonist (SAG), or Shh plus the Smo inhibitors SANT-1, cyclopamine (CP), or KAAD-cyclopamine (KAAD) (Chinchilla et al., 2010).
Figure 3.3
Figure 3.3
The three Hh isoforms promote tubulogenesis in endothelial cells by a Gi protein and RhoA-dependent mechanism. (A) HUVECs were cultured in a 3D collagen Type I matrix for 24h in the absence (control) or presence of Shh, Ihh, or Dhh (all at 2.5μg/ml). Photographs are representative tube densities. (B) Quantification of tube density in the absence (control) or presence of Shh, Ihh, and Dhh, and in the presence of Shh after preincubation with 0.5μM KAAD-cyclopamine (KAAD, Smo inhibitor) or 100ng/ml Pertussis toxin (PTX; inhibitor of Gi protein activation). (C) HUVECs were serum staved for 24h and stimulated with Shh, Ihh, or Dhh (all at 2.5μg/ml) during 15 min. Active RhoA (RhoA-GTP) was pulled down from whole cell lysates with a Rhotekin-binding domain–GST fusion protein coupled to GSH-sepharose beads. Active and total RhoA were evaluated by Western blot, and the densitometric values are shown in the bar graph (n=3). (D) RhoA pull-down assay as in (C) in cells preincubated with 0.5μM KAAD-cyclopamine (KAAD) or 100ng/ml PTX (n=3) (Chinchilla et al., 2010).
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References

    1. Adolphe C, Hetherington R, Ellis T, Wainwright B. Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res. 2006;66:2081–2088. - PubMed
    1. Barnes EA, Kong M, Ollendorff V, Donoghue DJ. Patched1 interacts with cyclin B1 to regulate cell cycle progression. EMBO J. 2001;20:2214–2223. - PMC - PubMed
    1. Barnes EA, Heidtman KJ, Donoghue DJ. Constitutive activation of the shh-ptc1 pathway by a patched mutation identified in BCC. Oncogene. 2005;24:902–915. - PubMed
    1. Belgacem YH, Borodinsky LN. Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord. Proc Natl Acad Sci USA. 2011;108:4482–4487. - PMC - PubMed
    1. Berridge MJ. Neuronal calcium signaling. Neuron. 1998;21:13–26. - PubMed

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