PMID- 20818436
OWN - NLM
STAT- MEDLINE
DCOM- 20110228
LR  - 20231213
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 30
IP  - 1
DP  - 2011 Jan 6
TI  - Numb activates the E3 ligase Itch to control Gli1 function through a novel 
      degradation signal.
PG  - 65-76
LID - 10.1038/onc.2010.394 [doi]
AB  - Hedgehog pathway regulates tissue patterning and cell proliferation. Gli1 
      transcription factor is the major effector of Hedgehog signaling and its 
      deregulation is often associated to medulloblastoma formation. Proteolytic 
      processes represent a critical mechanism by which this pathway is turned off. 
      Here, we characterize the regulation of an ubiquitin-mediated mechanism of Gli1 
      degradation, promoted by the coordinated action of the E3 ligase Itch and the 
      adaptor protein Numb. We show that Numb activates the catalytic activity of Itch, 
      releasing it from an inhibitory intramolecular interaction between its homologous 
      to E6-AP C-terminus and WW domains. The consequent activation of Itch, together 
      with the recruitment of Gli1 through direct binding with Numb, allows Gli1 to 
      enter into the complex, resulting in Gli1 ubiquitination and degradation. This 
      process is mediated by a novel Itch-dependent degron, composed of a combination 
      of two PPXYs and a phospho-serine/proline motifs, localized in Gli1 C-terminal 
      region, indicating the role of two different WW docking sites in Gli1 
      ubiquitination. Remarkably, Gli1 protein mutated in these modules is no longer 
      regulated by Itch and Numb, and determines enhanced Gli1-dependent 
      medulloblastoma growth, migration and invasion abilities, as well as in vitro 
      transforming activity. Our data reveal a novel mechanism of regulation of Gli1 
      stability and function, which influences Hedgehog/Gli1 oncogenic potential.
FAU - Di Marcotullio, L
AU  - Di Marcotullio L
AD  - Department of Molecular Medicine, Sapienza University, Rome, Italy.
FAU - Greco, A
AU  - Greco A
FAU - Mazza, D
AU  - Mazza D
FAU - Canettieri, G
AU  - Canettieri G
FAU - Pietrosanti, L
AU  - Pietrosanti L
FAU - Infante, P
AU  - Infante P
FAU - Coni, S
AU  - Coni S
FAU - Moretti, M
AU  - Moretti M
FAU - De Smaele, E
AU  - De Smaele E
FAU - Ferretti, E
AU  - Ferretti E
FAU - Screpanti, I
AU  - Screpanti I
FAU - Gulino, A
AU  - Gulino A
LA  - eng
GR  - GGP07118/TI_/Telethon/Italy
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100906
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (GLI1 protein, human)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (NUMB protein, human)
RN  - 0 (Repressor Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Ubiquitin)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - EC 2.3.2.26 (ITCH protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Animals
MH  - Hedgehog Proteins/metabolism
MH  - Humans
MH  - Membrane Proteins/*metabolism
MH  - Mice
MH  - NIH 3T3 Cells
MH  - Nerve Tissue Proteins/*metabolism
MH  - Repressor Proteins/metabolism
MH  - Signal Transduction
MH  - Transcription Factors/*metabolism
MH  - Ubiquitin/metabolism
MH  - Ubiquitin-Protein Ligases/genetics/*metabolism
MH  - Zinc Finger Protein GLI1
EDAT- 2010/09/08 06:00
MHDA- 2011/03/01 06:00
CRDT- 2010/09/07 06:00
PHST- 2010/09/07 06:00 [entrez]
PHST- 2010/09/08 06:00 [pubmed]
PHST- 2011/03/01 06:00 [medline]
AID - onc2010394 [pii]
AID - 10.1038/onc.2010.394 [doi]
PST - ppublish
SO  - Oncogene. 2011 Jan 6;30(1):65-76. doi: 10.1038/onc.2010.394. Epub 2010 Sep 6.