Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2008) Nucleic Acids Res , doi:10.1093/nar/gkn808

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ITAM Immunoreceptor tyrosine-based activation motif

There are 184 ITAM domains in 141 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a ITAM domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with ITAM domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Homo sapiens, Mus musculus, Rattus norvegicus, Takifugu rubripes

• Cellular role (predicted cellular role)

• Binding / catalysis: SH2 domain-binding when tyrosine-phosphorylated

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Post CB, Gaul BS, Eisenmesser EZ, Schneider ML
  • NMR structure of phospho-tyrosine signaling complexes.
  • Med Res Rev. 1999; 19: 295-305
  • Display abstract

  • A structural basis for activation and substrate specificity of src tyrosine kinases, and regulation of protein-protein association by tyrosine phosphorylation is described. Lyn, a src-family tyrosine kinase, recognizes and phosphorylates the immunoreceptor tyrosine-based activation motif, ITAM, a critical component in transmembrane signal transduction in hemopoietic cells. The structure of an ITAM peptide substrate bound to an active form of Lyn tyrosine kinase was determined by high-resolution NMR, and a model of the complex was generated using the crystallographic structure of Lck, a closely related Src-family kinase. The results provide a rationale for the conserved ITAM residues and specificity of Lyn, and suggest that substrate plays a role in stabilizing the kinase conformation optimal for catalysis. It is our hope that the Lck-ITAM peptide model complex will be useful in aiding structure-based drug design efforts that target substrate binding determinants in the design. Concerning the regulation of protein-protein association, we report on a complex between erythrocyte band 3 and two glycolytic enzymes, aldolase and glyceraldehyde-3-phosphate dehydrogenase. The formation of this complex is negatively regulated by tyrosine phosphorylation of band 3 by p72syk tyrosine kinase. In red blood cells, this association results in a decrease in glycolysis due to competitive inhibition of the glycolytic enzymes. The structure of band 3 recognized by the glycolytic enzymes was determined by solution NMR, and found to be a loop structure with tyrosine centrally positioned and excluded from intermolecular contact. This phosphorylation sensitive interaction, or PSI, loop may be the basis of a general mechanism for negative regulation through tyrosine phosphorylation.

  • Johnson SA, Pleiman CM, Pao L, Schneringer J, Hippen K, Cambier JC
  • Phosphorylated immunoreceptor signaling motifs (ITAMs) exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases.
  • J Immunol. 1995; 155: 4596-603
  • Display abstract

  • Signal transduction by T and B cell Ag receptors and certain receptors for Ig Fc regions (Fc gamma RI, hFc gamma RIIA, Fc gamma RIII, Fc alpha R, and Fc epsilon RI) involves a conserved sequence motif, termed an immunoreceptor tyrosine-based activation motif (ITAM) and found in multiple receptor chains. Phosphorylation of the two ITAM tyrosines is a critical event in signal transduction. To address the function of this phosphorylation, we assessed the ability of nonphosphorylated and biphosphorylated ((p)2ITAM) ITAM peptides to bind and modify the activity of src and syk family kinases in vivo and in vitro. All (p)2ITAMs, but not their nonphosphorylated counterparts, induced extensive protein tyrosine phosphorylation in permeabilized cells. However, the patterns of proteins phosphorylated differed among (p)2ITAMs. This phosphorylation was found to reflect activation of the src family kinase Lyn, but not Syk. In vitro studies using purified Lyn showed that src family kinase activation resulted from a direct interaction with (p)2ITAM. Binding studies demonstrated clear differences in binding specificity of (p)2ITAMs. Most strikingly, Ig alpha (p)2ITAM and TCR-zeta c and CD3 epsilon (p)2ITAMs exhibit inverse binding preferences for src and syk family kinases. Taken together, these findings demonstrate a novel mechanism by which src family tyrosine kinases are activated, and are consistent with the possibility that different ITAMs may preferentially activate distinct signaling pathways as a consequence of distinct effector Src homology 2 domain (SH2) binding preference.

  • Reth M
  • Antigen receptor tail clue.
  • Nature. 1989; 338: 383-4
• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 37.18 map04660 T cell receptor signaling pathway 28.21 map04640 Hematopoietic cell lineage 15.38 map04662 B cell receptor signaling pathway 14.10 map04650 Natural killer cell mediated cytotoxicity 5.13 map04664 Fc epsilon RI signaling pathway This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with ITAM domain which could be assigned to a KEGG orthologous group, and not all proteins containing ITAM domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of ITAM domains in PDB

  PDB code	Main view	Title
  2k4f
  2oq1		Tandem sh2 domains of zap-70 with 19-mer zeta1 peptide

• Links (links to other resources describing this domain)

• INTERPRO	IPR003110