Regulation of Hedgehog signaling by ubiquitination

Abstract

The Hedgehog (Hh) signaling pathway plays crucial roles both in embryonic development and in adult stem cell function. The timing, duration and location of Hh signaling activity need to be tightly controlled. Abnormalities of Hh signal transduction lead to birth defects or malignant tumors. Recent data point to ubiquitination-related posttranslational modifications of several key Hh pathway components as an important mechanism of regulation of the Hh pathway. Here we review how ubiquitination regulates the localization, stability and activity of the key Hh signaling components.

Keywords: Hedgehog signaling; ubiquitination.

Figure 1. Regulation of Hedgehog signaling by ubiquitination

(A) In Drosophila, dPtc localized at the plasma membrane suppresses dSmo activity in the absence of Hh. An unknown E3 ligase (E3?) promotes internalization and degradation of dSmo. Sufu sequesters full-length Ci (Ci^FL) in the cytoplasm and protects Ci^FL from spurious Cul3-HIB-mediated degradation. Ci^FL is also targeted by Cul1-Slimb for partial degradation to the repressor form Ci^R leading to repression of pathway target genes. Nuclear export of the spliceosome factor Crn by an unknown substrate (S) allows functional Sufu mRNA to be translated. (B) Hh binding to dPtc releases its inhibition on dSmo. UBPY/USP8 reverses dSmo ubiquitination and promotes dSmo accumulation at the plasma membrane, although this can also occur in the absence of Hh. Activated dSmo recruits Smurf to the plasma membrane where Smurf mediates the internalization and degradation of dPtc. Cul1-Slimb-mediated Ci^R formation is inhibited, allowing for formation of the activator form Ci^A and activation of pathway target genes including hib. HIB functions in a negative feedback manner by promoting the degradation of Ci^FL. Cul3-HIB also targets the unknown substrate S for degradation, allowing Crn to accumulate in the nucleus where it inhibits formation of functional Sufu mRNA and leads to reduced Sufu protein synthesis. (C) In vertebrates, in the absence of Hh ligands, Ptch1 suppresses activation of vSmo, which is internalized and degraded by an unknown E3 ligase. Sufu protects full-length Gli2 and Gli3 (Gli^FL) from Cul3-Spop-mediated degradation. Sufu also promotes the partial degradation of Gli^FL to Gli^R by Cul1-βTrCP. (D) In the presence of Hh ligands, Ptch1 is internalized and degraded by Smurf1/2. An unknown deubiquitinase (DUB) decreases vSmo ubiquitination and degradation. Sufu is degraded in a Cul3-Spop-dependent manner, and Gli^R formation by Cul1-βTrCP is inhibited, allowing for Gli^A formation.