The E3 Ubiquitin Ligase MID1 Catalyzes Ubiquitination and Cleavage of Fu

Susann Schweiger,Stephanie Dorn,Melanie Fuchs,Andrea Köhler,Frank Matthes,Eva-Christina Müller,Erich Wanker,Rainer Schneider,Sybille Krauß

doi:10.1074/jbc.m113.541219

Abstract

SHH (Sonic Hedgehog)-GLI signaling plays an important role during embryogenesis and in tumorigenesis. The survival and growth of several types of cancer depend on autonomously activated SHH-GLI signaling. A protein complex containing the ubiquitin ligase MID1 and protein phosphatase 2A regulates the nuclear localization and transcriptional activity of GLI3, a transcriptional effector molecule of SHH, in cancer cell lines with autonomously activated SHH signaling. However, the exact molecular mechanisms that mediate the interaction between MID1 and GLI3 remained unknown. Here, we show that MID1 catalyzes the ubiquitination and proteasomal cleavage of the GLI3 regulator Fu. Our data suggest that Fu ubiquitination and cleavage is one of the key elements connecting the MID1-PP2A protein complex with GLI3 activity control.

Highlights

SHH signaling is an important growth-stimulating factor in diverse cancers
Because the Fu kinase promotes the nuclear localization of GLI proteins [11] and is up-regulated in cancer cells [20], we tested for a putative involvement of Fu in the regulation of GLI3 subcellular localization and activity
We show that human Fu controls the subcellular localization and transcriptional activity of GLI3 in cancer cell lines

Summary

Background

SHH signaling is an important growth-stimulating factor in diverse cancers. Results: MID1 catalyzes ubiquitination and proteasomal cleavage of Fu. Conclusion: The MID1-PP2A complex regulates the activity of the SHH effector GLI3 in cancer cell lines by regulating proteasomal cleavage of Fu. Significance: Understanding the molecular mechanisms underlying tumorigenesis is crucial for developing therapeutic approaches to treat cancers. A protein complex containing the ubiquitin ligase MID1 and protein phosphatase 2A regulates the nuclear localization and transcriptional activity of GLI3, a transcriptional effector molecule of SHH, in cancer cell lines with autonomously activated SHH signaling. In Drosophila, the cytosolic transduction of the Hh signal involves a microtubule-associated protein complex containing Fu (Fused), the GLI family transcription factor Ci (Cubitus Interruptus), the kinesin-like protein Cos (Costal2), and SuFu (Suppressor of Fused) (reviewed in Ref. 4).

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EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION