SMURF1/2 bind PTCH1

Stable Identifier
R-HSA-5632646
Type
Reaction [binding]
Species
Homo sapiens
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Hh stimulation promotes PTCH1 clearance from the primary cilium to endocytic compartments (Rohatgi et al, 2007; reviewed in Nowaza et al, 2013). Receptor internalization is required for pathway activation, and additionally limits the duration and range of Hh signaling by sequestering the ligand inside the cell (Rohatgi et al, 2007; Incardona et al, 2000; Incardona et al, 2002; Denef et al, 2000; Huang et al, 2013; Yue et al, 2014). Upon Hh pathway activation, the E3 ligases SMURF1 and SMURF2 bind to two PPXY motifs in the C-terminal tail of PTCH1 to promote its ubiquination, endocytosis and degradation. In Drosophila, SMURF-mediated ubiquitination of PTCH is depends on an interaction between SMURF and activated SMO, but this does not appear to be true in vertebrates where PTCH1 turnover is SMO-independent (Yue et al, 2014; Huang et al, 2013; Lu et al, 2006). In flies, SMURF-dependent ubiquitination preferentially downregulates ligand-unbound receptor and is thus believed to regulate downstream signaling by altering the ratio of bound to unbound receptor on the cell surface; this aspect of PTCH1 downregulation has not been examined in detail in vertebrate cells (Huang et al, 2013; Casali and Struhl, 2004; Yue et al, 2014).

Literature References
PubMed ID Title Journal Year
12123571 Sonic hedgehog induces the segregation of patched and smoothened in endosomes

Incardona, JP, Gruenberg, J, Roelink, H

Curr. Biol. 2002
16980583 The C-terminal tail of the Hedgehog receptor Patched regulates both localization and turnover

Lu, X, Liu, S, Kornberg, TB

Genes Dev. 2006
23725801 Hedgehog signaling from the primary cilium to the nucleus: an emerging picture of ciliary localization, trafficking and transduction

Nozawa, YI, Lin, C, Chuang, PT

Curr. Opin. Genet. Dev. 2013
15300262 Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein

Casali, A, Struhl, G

Nature 2004
24925320 Requirement of Smurf-mediated endocytosis of Patched1 in Sonic Hedgehog signal reception

Yue, S, Tang, LY, Tang, Y, Tang, Y, Shen, QH, Ding, J, Chen, Y, Zhang, Z, Yu, TT, Zhang, YE, Cheng, SY

Elife 2014
24302888 Activation of Smurf E3 ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover

Huang, S, Zhang, Z, Zhang, C, Lv, X, Zheng, X, Chen, Z, Sun, L, Wang, H, Zhu, Y, Zhang, J, Yang, S, Lu, Y, Sun, Q, Tao, Y, Liu, F, Zhao, Y, Chen, D

PLoS Biol. 2013
10966113 Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened

Denef, N, Neub├╝ser, D, Perez, L, Cohen, SM

Cell 2000
11027307 Receptor-mediated endocytosis of soluble and membrane-tethered Sonic hedgehog by Patched-1

Incardona, JP, Lee, JH, Robertson, CP, Enga, K, Kapur, RP, Roelink, H

Proc. Natl. Acad. Sci. U.S.A. 2000
17641202 Patched1 regulates hedgehog signaling at the primary cilium

Rohatgi, R, Milenkovic, L, Scott, MP

Science 2007
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