Article

Shifting paradigms in Hedgehog signaling

Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
Current Opinion in Cell Biology (Impact Factor: 8.47). 05/2007; 19(2):159-65. DOI: 10.1016/j.ceb.2007.02.005
Source: PubMed

ABSTRACT

Hedgehog (Hh) signaling proteins regulate multiple developmental and adult homeostatic processes. A defining feature of Hh signaling is that relatively small changes in the concentration of Hh ligand elicit dramatically different cellular responses. As a result, the processing, release and trafficking of Hh ligands must be tightly regulated to ensure proper signaling. In addition, sensitive and specific intracellular signaling cascades are needed to interpret subtle differences in the level of Hh signal to execute an appropriate response. A detailed understanding of the mechanisms that regulate these responses is critical to shaping our view of this key regulatory system.

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    • "It is thought that SMO/EVC/ EVC2 interact with SUFU thereby resolving the SUFU/ GLI3 inhibitory complex [57]. In consequence, GLI3 proteolytic processing is prevented leading to a weak activator form of GLI3 that translocates to the nucleus [58]. Active GLI3 up-regulates the expression of the transcriptional activator GLI1 that, although apparently not involved in the initial Hh dependent response of the pathway, is a strong potentiator of the signal [54] [59] "
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    ABSTRACT: The Hedgehog (HH) signaling pathway is critical in embryonic development, stem cell biology, tissue homeostasis, chemoattraction and synapse formation. Irregular HH signaling is associated with a number of disease conditions including congenital disorders and cancer. In particular, deregulation of HH signaling has been linked to skin, brain, lung, colon and pancreatic cancers. Key mediators of the HH signaling pathway are the 12-pass membrane protein Patched (PTC), the 7-pass membrane protein Smoothened (SMO) and the GLI transcription factors. PTC shares homology with the RND family of small-molecule transporters and it has been proposed that it interferes with SMO through metabolites. Although a conclusive picture is lacking, substantial efforts are made to identify and understand natural metabolites/sterols, including cholesterol, vitamin D3, oxysterols and glucocorticoides, that may be affected by, or influence the HH signaling cascade at the level of PTC and SMO. In this review we will elaborate the role of metabolites in HH signaling with a focus on oxysterols, and discuss advancements in modern analytical approaches in the field.
    Full-text · Article · Jan 2014 · Biochemical and Biophysical Research Communications
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    • "It is thought that SMO/EVC/ EVC2 interact with SUFU thereby resolving the SUFU/ GLI3 inhibitory complex [57]. In consequence, GLI3 proteolytic processing is prevented leading to a weak activator form of GLI3 that translocates to the nucleus [58]. Active GLI3 up-regulates the expression of the transcriptional activator GLI1 that, although apparently not involved in the initial Hh dependent response of the pathway, is a strong potentiator of the signal [54] [59] "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hedgehog (HH) signaling pathway is critical in embryonic development, stem cell biology, tissue homeostasis, chemoattraction and synapse formation. Irregular HH signaling is associated with a number of disease conditions including congenital disorders and cancer. In particular, deregulation of HH signaling has been linked to skin, brain, lung, colon and pancreatic cancers. Key mediators of the HH signaling pathway are the 12-pass membrane protein Patched (PTC), the 7-pass membrane protein Smoothened (SMO) and the GLI transcription factors. PTC shares homology with the RND family of small-molecule transporters and it has been proposed that it interferes with SMO through metabolites. Although a conclusive picture is lacking, substantial efforts are made to identify and understand natural metabolites/sterols, including cholesterol, vitamin D3, oxysterols and glucocorticoides, that may be affected by, or influence the HH signaling cascade at the level of PTC and SMO. In this review we will elaborate the role of metabolites in HH signaling with a focus on oxysterols, and discuss advancements in modern analytical approaches in the field.
    Full-text · Article · Jan 2014 · Biochemical and Biophysical Research Communications
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    • "The mammalian Hh ligands, Sonic (Shh), Indian (Ihh) and Desert (Dhh), bind to twelve-pass transmembrane receptors Patched (Ptch1, Ptch2) on neighboring cells [26], [27]. This event relieves the seven-pass transmembrane protein smoothened (Smo) from Ptch-mediated repression and generates signals that are transduced by the Gli family of transcriptional activators and repressors (Gli1-3) [27], [28], [29]. Downstream Gli target genes, Ptch and Hhip (Hedgehog interacting protein), together with molecules acting at the level of ligand-binding such as cell surface bound Ig/fibronectin family members Cdo and Boc provide feedback mechanisms at various levels to keep the pathway in check [30]. "
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    ABSTRACT: Gli3 is a transcriptional regulator of Hedgehog (Hh) signaling that functions as a repressor (Gli3(R)) or activator (Gli3(A)) depending upon cellular context. Previously, we have shown that Gli3(R) is required for the formation of mammary placodes #3 and #5. Here, we report that this early loss of Gli3 results in abnormal patterning of two critical regulators: Bmp4 and Tbx3, within the presumptive mammary rudiment (MR) #3 zone. We also show that Gli3 loss leads to failure to maintain mammary mesenchyme specification and loss of epithelial Wnt signaling, which impairs the later development of remaining MRs: MR#2 showed profound evagination and ectopic hairs formed within the presumptive areola; MR#4 showed mild invagination defects and males showed inappropriate retention of mammary buds in Gli3(xt/xt) mice. Importantly, mice genetically manipulated to misactivate Hh signaling displayed the same phenotypic spectrum demonstrating that the repressor function of Gli3(R) is essential during multiple stages of mammary development. In contrast, positive Hh signaling occurs during nipple development in a mesenchymal cuff around the lactiferous duct and in muscle cells of the nipple sphincter. Collectively, these data show that repression of Hh signaling by Gli3(R) is critical for early placodal patterning and later mammary mesenchyme specification whereas positive Hh signaling occurs during nipple development.
    Preview · Article · Nov 2013 · PLoS ONE
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