Hedgehog Induces Opposite Changes in Turnover and Subcellular Localization of Patched and Smoothened

Denef, Natalie; Neubüser, Dagmar; Pérez, Lídia; Cohen, Stephen M.

doi:10.1016/s0092-8674(00)00056-8

Cited by 484 publications

(517 citation statements)

References 51 publications

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“…Other studies depict the internalization of Ptc and hedgehog into intracellular vesicles, while Smo accumulates at the cell surface [9,18,27,28]. The phosphorylation of Smo following Ihh binding to Ptc may also play a role in Smo activation [9]. Smo then acts as the main signaling component of the Ihh receptor complex, resulting in Gli activation [19].…”

Section: Discussionmentioning

confidence: 99%

Expression patterns of hedgehog signaling peptides in naturally acquired equine osteochondrosis

Semevolos

Strassheim

Haupt

et al. 2005

Journal Orthopaedic Research

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Hypertrophic differentiation and endochondral ossification of growth cartilage are regulated by a complex array of signaling peptides, including parathyroid hormone-related protein (PTH-rP), Indian hedgehog (Ihh), and bone morphogenetic proteins (BMPs). This study investigated the expression of Ihh, Patched1 and 2 (Ptcl, Ptc2), Smoothened (Smo), Glil, and Gli3, in naturally acquired articular osteochondrosis, using an equine model. Cartilage was harvested from osteochondrosis (OC) affected femoropatellar or scapulohumeral joints from immature horses and normal control horses of similar age. Ihh, Ptcl, Smo, Glil, and Gli3 mRNA expression levels were evaluated by real-time quantitative PCR. Spatial tissue expression was determined by in situ hybridization for Ihh and Smo and immunohistochemistry for Ptcl and Ptc2. The expression of Ihh was significantly increased in OC cartilage compared to normal control cartilage and was localized mainly to the deep layer of articular cartilage, just above the calcified zone, with some mild expression also present in the middle cartilage layer. The expression of Glil was significantly decreased in OC samples, but there was no significant difference in expression of Gli3, Ptcl and Smo in OC cartilage compared to normal cartilage. The expression of Ptcl protein was present at the junction of deep and calcified layers, while Ptc2 protein was expressed throughout the middle, deep, and calcified cartilage layers. Spatial expression of Smo was variable between animals and confined mainly to the middle and deep layers when present. Half of the OC samples displayed areas of moderate to strong Smo expression compared to mild or minimal expression in normal controls. The increased Ihh expression in OC suggests a role of Ihh in diseased cartilage, although it is not known if a PTHrP/Ihh feedback cycle exists in articular cartilage. The disparity between increased Ihh expression and decreased Glil expression in OC cartilage suggests a different primary transcription factor for Ihh or the presence of an elevated Ihh inhibitor in these tissues.

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Section: Discussionmentioning

confidence: 99%

Expression patterns of hedgehog signaling peptides in naturally acquired equine osteochondrosis

Semevolos

Strassheim

Haupt

et al. 2005

Journal Orthopaedic Research

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“…In response to Hh, it is phosphorylated and stabilized to allow for activation of the signaling cascade [39,42]. Both stabilization and phosphorylation appear to be actively repressed by Ptc, as these Smo modifications can occur in response to Ptc dysfunction or loss [39,42,43]. Conversely, over-expression of Ptc reduces Smo concentration and phosphorylation in both embryos and wing discs [39,43,44].…”

Section: Smoothenedmentioning

confidence: 99%

“…Both stabilization and phosphorylation appear to be actively repressed by Ptc, as these Smo modifications can occur in response to Ptc dysfunction or loss [39,42,43]. Conversely, over-expression of Ptc reduces Smo concentration and phosphorylation in both embryos and wing discs [39,43,44]. Ptc appears to function catalytically in repression and destabilization of Smo, as Ptc can block Smo signaling at substochiometric levels [45].…”

Section: Smoothenedmentioning

confidence: 99%

“…Changes in Smo subcellular localization correlate with its conversion to an active signaling molecule. In cells not receiving Hh, Smo localizes to discrete endosomal vesicles, where it is believed to be degraded [39,47]. In response to Hh, Smo moves from internal structures to the plasma membrane (PM), presumably to activate the signaling cascade [39,44,47].…”

Section: Smoothenedmentioning

confidence: 99%

“…While this process has yet to be clearly demonstrated, Hh has been demonstrated to affect Ptc subcellular localization. Binding by Hh has been documented to decrease the amount of Ptc on the plasma membrane (PM) [39]. This is achieved primarily through internalization of Hhbound Ptc into endocytic vesicles [35,40].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Hedgehog signaling: a complex story

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The Hedgehog (Hh) signal transduction pathway plays critical instructional roles during development. Activating mutations in human Hh signaling components predispose to a variety of tumor types, and have been observed in sporadic tumors occurring in a wide range of organs. Multiple insights into the regulation of Hh signaling have been achieved through studies using Drosophila melanogaster as a model organism. In Drosophila, regulation of the transcription factor

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Analysis of Smoothened as a candidate gene for human holoprosencephaly

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deSauvage

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Gene Funct. Dis.

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Holoprosencephaly (HPE) is the most common structural congenital forebrain malformation in humans and is associated with mental retardation and craniofacial abnormalities. In HPE, the cerebral hemispheres fail to separate into distinct right and left halves. The condition is etiologically heterogeneous, as multiple genes and environmental factors are associated with the condition. Autosomal dominant HPE can be caused by mutations in Sonic Hedgehog (SHH). Smoothened (SMOH; human gene) encodes a transmembrane protein that acts in SHH signal transduction. Because of the critical role of SMOH in the SHH pathway, we performed mutation analysis of this gene in familial and sporadic cases of HPE. Although we identified a number of nucleotide changes in SMOH in affected patients, none of these changes is likely to be pathogenic. Thus, haploinsufficiency for SMOH is unlikely to be a significant cause of human HPE in live‐born infants.

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Hedgehog Induces Opposite Changes in Turnover and Subcellular Localization of Patched and Smoothened

Cited by 484 publications

References 51 publications

Expression patterns of hedgehog signaling peptides in naturally acquired equine osteochondrosis

Expression patterns of hedgehog signaling peptides in naturally acquired equine osteochondrosis

Regulation of Hedgehog signaling: a complex story

Analysis of Smoothened as a candidate gene for human holoprosencephaly

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