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Gene Review

ITCH  -  itchy E3 ubiquitin protein ligase

Homo sapiens

Synonyms: ADMFD, AIF4, AIP4, Atrophin-1-interacting protein 4, E3 ubiquitin-protein ligase Itchy homolog, ...
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Disease relevance of ITCH

  • We also show that WWP1, WWP2, or Itch ubiquitin ligase recruitment promotes PPXY-dependent virion release, and that this function requires that the HECT ubiquitin ligase domain be catalytically active [1].
  • Third, the compromise of effector T cell function is mediated by the enhanced induction of anergy-inducing factors cbl-b, c-cbl (cbl is abbreviation for Casitas B lymphoma), Itch, and Nedd4 [2].
  • The fact that, even after pertussis toxin treatment, direct G-protein activation by AIF4- was still able to trigger a cytosolic free Ca2+ transient, indicates that, in these cells, G-proteins (GTP-binding proteins) that are insensitive to pertussis toxin are capable of mediating a Ca2+ signal [3].
  • Contact sensitivity to NAPP printing plates secondary to a relapsing hand dermatitis [4].
  • Symptoms were measured using the Psoriasis Symptom Assessment (PSA) and an Itch scale [5].

Psychiatry related information on ITCH

  • There was a strong inverse correlation between physical activity (assessed over 6 days) and fatigue (P<0.005), but not between physical activity and Itch [6].
  • Methods. A consecutive sample of 109 dermatology inpatients with the symptom of pruritus were examined by interviews with consecutive ratings by experts (using psychiatric ICD-10 diagnoses, the Global Assessment of Functioning Scale and the Impairment Score) and self-assessment using the the Eppendorf Itch Questionnaire [7].

High impact information on ITCH

  • Deficiency or mutation of some of the E3s like Cbl, Cbl-b, or Itch, causes abnormal immune responses such as autoimmunity, malignancy, and inflammation [8].
  • Previous studies suggested that the a18H mutation results from a paracentric inversion that affects two loci: agouti and another, as yet unidentified locus designated itchy (the provisional gene symbol is Itch), that is responsible for the immunological phenotype of a18H mice [9].
  • The crystal structure has been determined for the complex between the Fe-protein and MoFe-protein components of nitrogenase stabilized by ADP x AIF4-, previously used as a nucleoside triphosphate analogue in nucleotide-switch proteins [10].
  • However, the product of the proto-oncogene ras in its guanosine diphosphate (GDP)-bound form interacted with AIF4 - in the presence of stoichiometric amounts of either of the guanosine triphosphatase (GTPase)-activating proteins (GAPs) p120GAP and neurofibromin [11].
  • Several HECT and RING E3 proteins have now also been linked to the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL, Itch and Nedd4 each negatively regulate T cell growth factor production and proliferation [12].

Biological context of ITCH


Anatomical context of ITCH

  • Predicted peptide sequence and chromosomal mapping identified the cloned molecule to be the product of the human ortholog of the mouse Itch gene, which has been implicated previously in the regulation of growth and differentiation of erythroid and lymphoid cells [18].
  • Ubiquitin-mediated fluorescence complementation reveals that Jun ubiquitinated by Itch/AIP4 is localized to lysosomes [19].
  • We show here that both molecules interact and partially colocalize to endocytic vesicles, and that AIP4 targets DTX for lysosomal degradation [20].
  • Here, Itch was shown to associate with Notch, a protein involved in cell fate decision in many mammalian cell types, including cells in the immune system [21].
  • This stimulation could be reversed when the alpha subunits not activated by cholera toxin, i.e. alpha i/alpha o, were activated by GTP gamma S and [AIF4]-. Our results show that both inhibitory and stimulatory trimeric G-proteins on the TGN participate in the regulation of secretory vesicle formation [22].

Associations of ITCH with chemical compounds

  • Inhibition of lysosomal protein degradation by bafilomycin or chloroquine stabilized Jun but had no effect on the stability of mutated Jun that was not ubiquitinated by Itch/AIP4 [19].
  • Furthermore, AIP4-generated polyubiquitin chains are mainly conjugated through lysine 29 of ubiquitin in vivo, indicating a link between this type of chain and lysosomal degradation [20].
  • In the absence of AIF-4 or GTP gamma S, the channels exhibited rapid activation and deactivation [23].
  • We also employed the folding and recycling inhibitors dithiothreitol and AIF4-, and coimmunoprecipitation with calnexin antibodies [24].
  • With low thrombin concentrations or with AIF4-, the formation of inositol phosphates is immediately increased with a marked reduction of the initial lag, whereas at high thrombin concentrations, the stimulation by FGF becomes pronounced only after desensitization of phospholipase C to thrombin [25].

Physical interactions of ITCH

  • Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2 [26].
  • Under normal conditions, the Runx-Yap1 complex binds the Itch promoter and supports its transcription and p73 degradation [27].

Enzymatic interactions of ITCH

  • Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro [28].

Other interactions of ITCH

  • Here we report our studies that demonstrate the function of AIP4 as an ubiquitin E3 ligase for HEF1 [13].
  • Consistent with this notion, expression of a catalytic mutant of AIP4, which is unable to induce ubiquitination and degradation of Smad7, also stabilizes the TbetaRI.Smad7 complex, resulting in inhibition of TGF-beta signaling [29].
  • Interaction between two ubiquitin-protein isopeptide ligases of different classes, CBLC and AIP4/ITCH [14].
  • The ability of AIP4 to enhance the inhibitory function of Smad7 independent of its ubiquitin ligase activity reveals a new mechanism by which E3 ubiquitin ligases may function to turn off TGF-beta signaling [29].
  • Both NEDD4 and Itch participate in the degradation of Melan-A [30].

Analytical, diagnostic and therapeutic context of ITCH

  • Our GST-pulldown and immunoprecipitation results indicate that RNF11 interacts with the E3 ligase AIP4 when coexpressed with RNF11 in mammalian cells [31].
  • Herein, we demonstrate that NT T cells significantly lose their ability to up-regulate inositol trisphosphate synthesis in response to TCR ligation or nonspecific activation of G proteins by AIF-4 [32].
  • Electrical Ear Acupuncture Reduces Histamine-induced Itch (Alloknesis) [33].
  • Stably selected clones were rapidly pre-screened for doxycycline (dox)-inducible BirA expression by ELISA, and subsequently screened for dox-inducible expression of biotinylated Itch [34].
  • The biotinylation of recombinant Itch in transiently transfected CHO Tet-On cells required biotin supplementation and coexpression of BirA, occurred quantitatively and specifically on the lysine residue of the BioTag, and enabled detection of Itch by Western blot in as little as 10ng of total lysate protein [34].


  1. HECT ubiquitin ligases link viral and cellular PPXY motifs to the vacuolar protein-sorting pathway. Martin-Serrano, J., Eastman, S.W., Chung, W., Bieniasz, P.D. J. Cell Biol. (2005) [Pubmed]
  2. Regulatory networks induced by live parasites impair both Th1 and Th2 pathways in patent lymphatic filariasis: implications for parasite persistence. Babu, S., Blauvelt, C.P., Kumaraswami, V., Nutman, T.B. J. Immunol. (2006) [Pubmed]
  3. Leukotriene D4 and E4 induce transmembrane signaling in human epithelial cells. Single cell analysis reveals diverse pathways at the G-protein level for the influx and the intracellular mobilization of Ca2+. Sjölander, A., Grönroos, E., Hammarström, S., Andersson, T. J. Biol. Chem. (1990) [Pubmed]
  4. Contact sensitivity to NAPP printing plates secondary to a relapsing hand dermatitis. Wahlberg, J.E. Contact Derm. (1983) [Pubmed]
  5. Impact of efalizumab on psoriasis-specific patient-reported outcomes. Results from three randomized, placebo-controlled clinical trials of moderate to severe plaque psoriasis. Menter, A., Kosinski, M., Bresnahan, B.W., Papp, K.A., Ware, J.E. Journal of drugs in dermatology : JDD. (2004) [Pubmed]
  6. Characterisation of the associations and impact of symptoms in primary biliary cirrhosis using a disease specific quality of life measure. Newton, J.L., Bhala, N., Burt, J., Jones, D.E. J. Hepatol. (2006) [Pubmed]
  7. Psychosomatic cofactors and psychiatric comorbidity in patients with chronic itch. Schneider, G., Driesch, G., Heuft, G., Evers, S., Luger, T.A., St??nder, S. Clin. Exp. Dermatol. (2006) [Pubmed]
  8. Ubiquitin ligases and the immune response. Liu, Y.C. Annu. Rev. Immunol. (2004) [Pubmed]
  9. The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Perry, W.L., Hustad, C.M., Swing, D.A., O'Sullivan, T.N., Jenkins, N.A., Copeland, N.G. Nat. Genet. (1998) [Pubmed]
  10. Structure of ADP x AIF4(-)-stabilized nitrogenase complex and its implications for signal transduction. Schindelin, H., Kisker, C., Schlessman, J.L., Howard, J.B., Rees, D.C. Nature (1997) [Pubmed]
  11. Formation of a transition-state analog of the Ras GTPase reaction by Ras-GDP, tetrafluoroaluminate, and GTPase-activating proteins. Mittal, R., Ahmadian, M.R., Goody, R.S., Wittinghofer, A. Science (1996) [Pubmed]
  12. E3 ubiquitin ligases as T cell anergy factors. Mueller, D.L. Nat. Immunol. (2004) [Pubmed]
  13. Atrophin-1-interacting protein 4/human Itch is a ubiquitin E3 ligase for human enhancer of filamentation 1 in transforming growth factor-beta signaling pathways. Feng, L., Guedes, S., Wang, T. J. Biol. Chem. (2004) [Pubmed]
  14. Interaction between two ubiquitin-protein isopeptide ligases of different classes, CBLC and AIP4/ITCH. Courbard, J.R., Fiore, F., Adélaïde, J., Borg, J.P., Birnbaum, D., Ollendorff, V. J. Biol. Chem. (2002) [Pubmed]
  15. Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination. Marcotullio, L.D., Ferretti, E., Greco, A., De Smaele, E., Po, A., Sico, M.A., Alimandi, M., Giannini, G., Maroder, M., Screpanti, I., Gulino, A. Nat. Cell Biol. (2006) [Pubmed]
  16. The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Marchese, A., Raiborg, C., Santini, F., Keen, J.H., Stenmark, H., Benovic, J.L. Dev. Cell (2003) [Pubmed]
  17. The HECT ubiquitin ligase AIP4 regulates the cell surface expression of select TRP channels. Wegierski, T., Hill, K., Schaefer, M., Walz, G. EMBO J. (2006) [Pubmed]
  18. Human ITCH is a coregulator of the hematopoietic transcription factor NF-E2. Chen, X., Wen, S., Fukuda, M.N., Gavva, N.R., Hsu, D., Akama, T.O., Yang-Feng, T., Shen, C.K. Genomics (2001) [Pubmed]
  19. Ubiquitin-mediated fluorescence complementation reveals that Jun ubiquitinated by Itch/AIP4 is localized to lysosomes. Fang, D., Kerppola, T.K. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  20. Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains. Chastagner, P., Isra??l, A., Brou, C. EMBO Rep. (2006) [Pubmed]
  21. Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase. Qiu, L., Joazeiro, C., Fang, N., Wang, H.Y., Elly, C., Altman, Y., Fang, D., Hunter, T., Liu, Y.C. J. Biol. Chem. (2000) [Pubmed]
  22. Multiple trimeric G-proteins on the trans-Golgi network exert stimulatory and inhibitory effects on secretory vesicle formation. Leyte, A., Barr, F.A., Kehlenbach, R.H., Huttner, W.B. EMBO J. (1992) [Pubmed]
  23. Identification of M-channels in outside-out patches excised from sympathetic ganglion cells. Stansfeld, C.E., Marsh, S.J., Gibb, A.J., Brown, D.A. Neuron (1993) [Pubmed]
  24. Quality control in the secretory pathway: retention of a misfolded viral membrane glycoprotein involves cycling between the ER, intermediate compartment, and Golgi apparatus. Hammond, C., Helenius, A. J. Cell Biol. (1994) [Pubmed]
  25. Tyrosine kinase-activating growth factors potentiate thrombin- and AIF4- -induced phosphoinositide breakdown in hamster fibroblasts. Evidence for positive cross-talk between the two mitogenic signaling pathways. Paris, S., Chambard, J.C., Pouysségur, J. J. Biol. Chem. (1988) [Pubmed]
  26. An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein. Li, H., Seth, A. Oncogene (2004) [Pubmed]
  27. A regulatory circuit controlling Itch-mediated p73 degradation by Runx. Levy, D., Reuven, N., Shaul, Y. J. Biol. Chem. (2008) [Pubmed]
  28. CISK attenuates degradation of the chemokine receptor CXCR4 via the ubiquitin ligase AIP4. Slagsvold, T., Marchese, A., Brech, A., Stenmark, H. EMBO J. (2006) [Pubmed]
  29. AIP4 restricts transforming growth factor-beta signaling through a ubiquitination-independent mechanism. Lallemand, F., Seo, S.R., Ferrand, N., Pessah, M., L'Hoste, S., Rawadi, G., Roman-Roman, S., Camonis, J., Atfi, A. J. Biol. Chem. (2005) [Pubmed]
  30. Ubiquitylation of a melanosomal protein by HECT-E3 ligases serves as sorting signal for lysosomal degradation. Lévy, F., Muehlethaler, K., Salvi, S., Peitrequin, A.L., Lindholm, C.K., Cerottini, J.C., Rimoldi, D. Mol. Biol. Cell (2005) [Pubmed]
  31. The RING-H2 protein RNF11 is differentially expressed in breast tumours and interacts with HECT-type E3 ligases. Kitching, R., Wong, M.J., Koehler, D., Burger, A.M., Landberg, G., Gish, G., Seth, A. Biochim. Biophys. Acta (2003) [Pubmed]
  32. Effects of nicotine on the immune response. II. Chronic nicotine treatment induces T cell anergy. Geng, Y., Savage, S.M., Razani-Boroujerdi, S., Sopori, M.L. J. Immunol. (1996) [Pubmed]
  33. Electrical Ear Acupuncture Reduces Histamine-induced Itch (Alloknesis). Kesting, M.R., Thurmueller, P., Hölzle, F., Wolff, K.D., Holland-Letz, T., Stücker, M. Acta Derm. Venereol. (2006) [Pubmed]
  34. A versatile system for site-specific enzymatic biotinylation and regulated expression of proteins in cultured mammalian cells. Kulman, J.D., Satake, M., Harris, J.E. Protein Expr. Purif. (2007) [Pubmed]
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