Disease relevance of Itch

• Epidermal overexpression of stratum corneum chymotryptic enzyme in mice: a model for chronic itchy dermatitis [1].
• BACKGROUND: Chronic idiopathic urticaria is a common skin disorder characterized by recurrent, transitory, itchy weals for more than 6 weeks [2].
• Although the possible involvement of neurotrophic factors in itchy skins of atopic dermatitis has been predicted, the exact mechanism by which itch is induced remains unclear [3].

High impact information on Itch

• We show that T cell activation promoted both Ndfip1 expression and its association with Itch [4].
• T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction [5].
• Itch is an E3 ubiquitin ligase that is disrupted in nonagouti-lethal or itchy mice [6].
• The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation [7].
• Importantly, tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB [7].

Biological context of Itch

• Itch promotes ubiquitination of Smad2 and augments Smad2 phosphorylation that requires an intact ligase activity of Itch [8].
• Allergic symptoms consist of rashes where animals are in contact with the skin, nasal congestion and sneezing, itchy eyes, and asthma (cough, wheezing, and chest tightness) [9].

Anatomical context of Itch

• Since Notch proteins have many important functions in the immune system, we determined whether Itch regulates Notch signaling in vivo [10].
• Itchy, a Nedd4 ubiquitin ligase, downregulates latent membrane protein 2A activity in B-cell signaling [11].
• Allergic rhinitis exerts inflammatory response and irritation of the nasal mucosal membranes leading to sneezing; stuffy/runny nose; nasal congestion; and itchy, watery and swollen eyes [12].
• Ultraviolet B reduces itchy sensation of uraemic patients by leading to depletion of cutaneous mast cells [13].

Associations of Itch with chemical compounds

• On cantharidin blister base experiments in humans, SP (10(-3) g/ml) produced slight pain and an itchy sensation [14].
• As compared with placebo supplementation, supplementation with extract of Perilla frutescens enriched for rosmarinic acid resulted in a significant increase in responder rates for itchy nose, watery eyes, itchy eyes, and total symptoms (P<0.05) [15].

Physical interactions of Itch

• Phosphorylation of the tyrosine within the PPXY motif by c-Abl inhibited c-Jun ubiquitination and its binding by Itch [16].

Other interactions of Itch

• Phylogenetic and in vitro analyses suggest that Itch is a negative regulator of Notch signaling [10].
• Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch [17].
• Homozygous itchy mice develop a fatal, late-onset autoimmune-like disease due to a loss of function mutation in an ubiquitin protein ligase [10].
• We have previously demonstrated that c-Jun is a substrate of Itch, a HECT-type E3 ubiquitin ligase. c-Jun is also a substrate of the tyrosine kinase c-Abl [16].

References