Decoding the Hedgehog signal in animal development

Jia, Jinping; Jen, Jin

doi:10.1007/s00018-005-5519-z

Cited by 96 publications

(90 citation statements)

References 201 publications

(248 reference statements)

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“…Three Hh family members have been identified in mammals including Sonic Hedgehog (Shh), Indian Hedgehog (Ihh) and Desert Hedgehog. Key components of the Hh signaling pathway include the 12-transmembrane receptor Patched (Ptc) that functions as the Hh receptor, the seven-transmembrane protein Smoothened (Smo) that functions as the obligated Hh signal transducer, and the Zincfinger transcription factor Cubitus interruptus (Ci)/Gli [4]. In the absence of Hh ligands, Ptc blocks the activity of Smo and full-length Ci/Gli is phosphorylated by multiple kinases including PKA, CK1 and GSK3β, which targets it for Slimb/β-TRCP-mediated proteolysis to generate its repressor form (Ci R /Gli R ) [5].…”

Section: Introductionmentioning

confidence: 99%

Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2

Yang

Chen

et al. 2012

Cell Res

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Section: Introductionmentioning

confidence: 99%

Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2

Yang

Chen

et al. 2012

Cell Res

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“…In Drosophila wing discs, HH proteins secreted by posterior (P) compartment cells move into the anterior (A) compartment to form a local concentration gradient 5,6 . Low levels of HH suffice to induce the expression of decapentaplegic (dpp), whereas high levels are required to induce patched (ptc) and engrailed (en) ( Supplementary Fig.…”

mentioning

confidence: 99%

Hedgehog regulates smoothened activity by inducing a conformational switch

Zhao¹,

Tong

Jen

2007

Nature

250

401

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Hedgehog (HH) morphogen is essential for metazoan development. The seven-transmembrane protein smoothened (SMO) transduces the HH signal across the plasma membrane, but how SMO is activated remains poorly understood. In Drosophila melanogaster, HH induces phosphorylation at multiple Ser/Thr residues in the SMO carboxy-terminal cytoplasmic tail, leading to its cell surface accumulation and activation. Here we provide evidence that phosphorylation activates SMO by inducing a conformational switch. This occurs by antagonizing multiple Arg clusters in the SMO cytoplasmic tail. The Arg clusters inhibit SMO by blocking its cell surface expression and keeping it in an inactive conformation that is maintained by intramolecular electrostatic interactions. HH-induced phosphorylation disrupts the interaction, and induces a conformational switch and dimerization of SMO cytoplasmic tails, which is essential for pathway activation. Increasing the number of mutations in the Arg clusters progressively activates SMO. Hence, by employing multiple Arg clusters as inhibitory elements counteracted by differential phosphorylation, SMO acts as a rheostat to translate graded HH signals into distinct responses.The HH morphogen controls many key development processes, with different thresholds specifying distinct outcomes [1][2][3][4] . In Drosophila wing discs, HH proteins secreted by posterior (P) compartment cells move into the anterior (A) compartment to form a local concentration gradient 5,6 . Low levels of HH suffice to induce the expression of decapentaplegic (dpp), whereas high levels are required to induce patched (ptc) and engrailed (en) ( Supplementary Fig. 1) [7][8][9] .The reception system for HH consists of a twelve-transmembrane protein, PTC, as the HH receptor and a seven-transmembrane protein smoothened (SMO) as the signal transducer 10-13 . In Drosophila, HH binding to PTC abrogates its inhibition on SMO and induces extensive phosphorylation of the SMO cytoplasmic tail by protein kinase A (PKA) and casein kinase I (CKI), leading to SMO cell surface accumulation and activation [14][15][16][17] . How phosphorylation promotes SMO cell surface accumulation is not understood. In addition, phosphorylation may regulate SMO activity through mechanism(s) other than controlling its cell surface abundance. Regulation of SMO by multiple Arg clustersOur previous study indicates that phosphorylation may regulate SMO cell surface abundance by either preventing its endocytosis and/or promoting its recycling 15 . To investigate further how SMO cell surface expression is regulated, we generated a set of C-terminally truncated SMO variants and examined their subcellular localization using a cell-based assay (Fig. 1). Deletion up to amino acid 818 did not significantly change SMO subcellular distribution; however, further deletions resulted in progressively increased cell surface expression (Fig. 1a, c), implying that multiple negative regulatory elements exist between amino acids 661-818.SMODC710 exhibits consistently higher cell surface...

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“…Low levels of Hh are able to induce the expression of dpp, whereas higher levels of Hh are also able to activate col and ptc. The induction of en appears to require the highest doses of Hh signaling activities (10,11).…”

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confidence: 99%

Hedgehog-regulated atypical PKC promotes phosphorylation and activation of Smoothened and Cubitus interruptus in Drosophila

Jiang

Liu

Fan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Hedgehog (Hh) signaling by Smoothened (Smo) is mediated by phosphorylation and cell surface/cilium accumulation, but how the localization of Smo is controlled remains poorly understood. We show that the atypical PKC (aPKC)–partition defective 6 (Par6) complex promotes Hh signaling by phosphorylating Smo and regulating Smo basolateral accumulation in addition to phosphorylating the transcription factor cubitus interruptus (Ci). Our results demonstrate direct involvement of aPKC in Hh signaling beyond its role in cell polarity and suggest that basolateral accumulation of Smo is critical for its activity. Abnormal activation of Smo results in several types of cancers, and Smo can easily acquire drug resistance through mutations. A better understanding of the mechanisms of Smo regulation is critical to developing more effective therapeutic treatments for cancers caused by Smo dysregulation.

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Decoding the Hedgehog signal in animal development

Cited by 96 publications

References 201 publications

Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2

Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2

Hedgehog regulates smoothened activity by inducing a conformational switch

Hedgehog-regulated atypical PKC promotes phosphorylation and activation of Smoothened and Cubitus interruptus in Drosophila

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