SnapShot: Hedgehog Signaling Pathway - Cardiovascular ...

386 Cell 130, July 27, 2007 ©2007 Elsevier Inc. DOI 10.1016/j.cell.2007.07.017 See online version for legend, abbreviations, and references.
SnapShot: Hedgehog Signaling Pathway
Miao-Hsueh Chen, Christopher W. Wilson, and Pao-Tien Chuang
Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA

SnapShot: Hedgehog
Signaling Pathway
Miao-Hsueh Chen, Christopher W. Wilson, and Pao-Tien Chuang
Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA
The Hedgehog (Hh) signal transduction pathway controls numerous processes during fly and vertebrate embryonic development and
adult homeostasis, including tissue/organ patterning, cellular proliferation and differentiation, pathfinding, left/right asymmetry, and
stem cell maintenance. Hh signaling is dysregulated in several congenital defects and many types of tumors. Hh is able to signal at
short-range but also may act as a long-range morphogen in multiple contexts (this aspect is controlled in part by lipid modification of
the Hh molecule). Hh signaling controls the balance of the transcriptional activator and repressor forms of Ci/Gli, the ratios of which are
essential for interpreting the level of Hh signal in a morphogenetic field and for generating diverse outputs.
Hh-Producing Cell
After translation, the Hh precursor enters the ER/Golgi secretory pathway. Autoproteolysis mediated by the C-terminal of Hh (Hh-C)
releases the N-terminal signaling peptide (Hh-N), with cholesterol covalently linked to its C terminus. Addition of a palmitate moiety to
the N terminus of the Hh signaling fragment is catalyzed by Skinny hedgehog (Ski/Skn). Lipid modifications are essential for the Hh
ligand to induce high-level signaling activity and proper formation of a morphogen gradient. Lipidated Hh is assisted in its release from
cells by Dispatched and possibly by the heparan sulfate proteoglycans (HSPGs) Dally and Dally-like (Dlp) and can be detected in distant
Hh-responsive cells. Although the mechanism of lipidated Hh-N release into the extracellular matrix is unknown, two soluble forms
of lipidated Hh-N have been detected including a multimeric protein complex in both flies and vertebrates and a lipoprotein particle
in flies. In flies, Hh in the extracellular matrix is protected from degradation by Shifted (Shf) and is funneled to its destination by Dlp.
Specific HSPG core proteins may play a role in vertebrate Hh signaling, but this has not yet been shown.
Hh-Responding Cell
Hh elicits transcriptional responses by binding to its trimeric receptor Patched (Ptc/Ptch1). Additional Hh coreceptors (Ihog family
members, HSPGs, and Gas1) may participate in induction of both transcription-dependent and -independent responses. Binding of
Hh to Ptc alleviates repression of Smoothened (Smo), allowing its translocation from endosomes to the cell surface in flies or to the
primary cilium in mice. Inhibition of Ptc results in phosphorylation of the cytosolic C-tail of Smo. Flies and vertebrates may use different
strategies downstream of Smo to modulate activity of the Ci/Gli transcription factors. In fly, recruitment of the atypical kinesin
Costal-2 (Cos-2)/Fused kinase (Fu)/Cubitus interruptus (Ci) complex to the phosphorylated Smo C-tail results in activation of the Ci
transcription factor, which then enters the nucleus and activates target gene expression. In vertebrates, generation of activated Gli
transcription factors involves the primary cilium, but it is currently unclear if a kinesin-like scaffold is an intermediary between Smo
and Gli. Numerous poorly characterized factors have been reported to play roles in modulating Gli activator and repressor activity. Two
general mechanisms exist to downregulate Hh signaling after the initial response. Ci/Gli transcription factors are ubiquitinated by Cullin
(Cul3) and HIB/SPOP complexes; the expression of Hh-binding proteins, such as Ptc and Hhip1, is upregulated to serve as a sink for
extracellular ligand.
Hh-Nonresponding Cell
In the absence of Hh ligand, Ptc inhibits Smo and prevents its translocation to the cell surface in flies or to the primary cilium in mice.
The nucleocytoplasmic distribution of newly synthesized Ci is controlled by the Ci/Gli-binding protein Sufu. In fly, microtubule-associated
Cos-2 serves as a scaffold for protein kinase A (PKA), casein kinase I (CKI), and glycogen synthase kinase 3 (GSK3), which phosphorylate
Ci. The SCF-Slimb-Cul1-Roc1a complex recognizes phosphorylated Ci and targets it for proteasome-dependent limited proteolysis,
which removes C-terminal transcriptional activation domains. The newly generated Ci repressor translocates to the nucleus
where it inhibits Hh target gene activation in conjunction with Sufu. In vertebrates, the primary cilium is involved in efficient generation
of Gli repressors, which are formed through a similar phosphorylation-dependent mechanism. Sufu may also mediate interactions
between Gli repressors and the HDAC1 repression complex.
Abbreviations
Arrb2, arrestin β2; Boc, cdo-binding protein; Boi, brother of ihog; Botv, brother of tout-velu; Cdo, cell adhesion molecule-related/downregulated
by oncogenes; Ext1/2, exostoses 1/2; Extl3, exostoses-like 3; Gas1, growth arrest specific-1; GRK2, G protein-coupled receptor kinase
2; HDAC1, histone deacetylase 1 complex; Ihog, interference hedgehog; IFT, intraflagellar transport; Igu/DZip1, iguana/DAZ interacting protein
1; MIM, missing in metastasis; Sotv, sister of tout-velu; SPOP, speckle-type POZ protein; Sufu, suppressor of fused; Ttv, tout-velu.
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386.e1 Cell 130, July 27, 2007 ©2007 Elsevier Inc. DOI 10.1016/j.cell.2007.07.017

SnapShot: Hedgehog
Signaling Pathway
Miao-Hsueh Chen, Christopher W. Wilson, and Pao-Tien Chuang
Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA
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386.e2 Cell 130, July 27, 2007 ©2007 Elsevier Inc. DOI 10.1016/j.cell.2007.07.017