PMID- 25714464
OWN - NLM
STAT- MEDLINE
DCOM- 20151116
LR  - 20161125
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 8
IP  - 365
DP  - 2015 Feb 24
TI  - The E3 ubiquitin ligase Itch inhibits p38alpha signaling and skin inflammation 
      through the ubiquitylation of Tab1.
PG  - ra22
LID - 10.1126/scisignal.2005903 [doi]
AB  - Deficiency in the E3 ubiquitin ligase Itch causes a skin-scratching phenotype in 
      mice. We found that there was increased phosphorylation and activation of the 
      mitogen-activated protein kinase p38alpha in spontaneous and experimentally induced 
      skin lesions of Itch-deficient (Itch-/-) mice. Itch bound directly to the 
      TGF-beta-activated kinase 1-binding protein 1 (Tab1) through a conserved PPXY motif 
      and inhibited the activation of p38alpha. Knockdown of Tab1 by short hairpin RNA 
      attenuated the prolonged p38alpha phosphorylation exhibited by Itch-/- cells. 
      Similarly, reconstitution of Itch-/- cells with wild-type Itch, but not the 
      ligase-deficient Itch-C830A mutant, inhibited the phosphorylation and activation 
      of p38alpha. Compared to the skin of wild-type mice, the skin of Itch-/- mice 
      contained increased amounts of the mRNAs of proinflammatory cytokines, including 
      tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1beta, IL-11, and IL-19. 
      Inhibition of p38 or blocking the interaction between p38alpha and Tab1 with a 
      cell-permeable peptide substantially attenuated skin inflammation in Itch-/- 
      mice. These findings provide insight into how Itch-mediated regulatory mechanisms 
      prevent chronic skin inflammation, which could be exploited therapeutically.
CI  - Copyright (c) 2015, American Association for the Advancement of Science.
FAU - Theivanthiran, Balamayooran
AU  - Theivanthiran B
AD  - Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 
      75204, USA.
FAU - Kathania, Mahesh
AU  - Kathania M
AD  - Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 
      75204, USA.
FAU - Zeng, Minghui
AU  - Zeng M
AD  - Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 
      75204, USA.
FAU - Anguiano, Esperanza
AU  - Anguiano E
AD  - Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 
      75204, USA.
FAU - Basrur, Venkatesha
AU  - Basrur V
AD  - Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
FAU - Vandergriff, Travis
AU  - Vandergriff T
AD  - Department of Dermatology, University of Texas Southwestern Medical Center, 
      Dallas, TX 75390, USA.
FAU - Pascual, Virginia
AU  - Pascual V
AD  - Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 
      75204, USA.
FAU - Wei, Wei-Zen
AU  - Wei WZ
AD  - Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 
      48201, USA.
FAU - Massoumi, Ramin
AU  - Massoumi R
AD  - Department of Laboratory Medicine, Lund University, Medicon Village, SE-22381 
      Lund, Sweden.
FAU - Venuprasad, K
AU  - Venuprasad K
AD  - Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 
      75204, USA. venuprasad.poojary@baylorhealth.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150224
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cytokines)
RN  - 0 (Tab1 protein, mouse)
RN  - EC 2.3.2.26 (Itch protein, mouse)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 14)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Animals
MH  - Cytokines/genetics/metabolism
MH  - Dermatitis/genetics/*metabolism/pathology
MH  - *MAP Kinase Signaling System
MH  - Mice
MH  - Mice, Knockout
MH  - Mitogen-Activated Protein Kinase 14/genetics/*metabolism
MH  - Phosphorylation/genetics
MH  - Skin/*metabolism/pathology
MH  - Ubiquitin-Protein Ligases/genetics/*metabolism
MH  - *Ubiquitination
EDAT- 2015/02/26 06:00
MHDA- 2015/11/17 06:00
CRDT- 2015/02/26 06:00
PHST- 2015/02/26 06:00 [entrez]
PHST- 2015/02/26 06:00 [pubmed]
PHST- 2015/11/17 06:00 [medline]
AID - 8/365/ra22 [pii]
AID - 10.1126/scisignal.2005903 [doi]
PST - epublish
SO  - Sci Signal. 2015 Feb 24;8(365):ra22. doi: 10.1126/scisignal.2005903.