Abstract
In an attempt to identify new immunoreceptor tyrosine-based activation motif (ITAM)-containing human molecules that may regulate hitherto unknown immune cell functions, we BLAST searched the National Center for Biotechnology Information database for ITAM-containing sequences. A human expressed sequence tag showing partial homology to the murine TJ6 (mTJ6) gene and encoding a putative ITAM sequence has been identified and used to clone the human TJ6 (hTJ6) gene from an HL-60-derived cDNA library. hTJ6 was found to encode a protein of 856 residues with a calculated mass of 98 155 Da. Immunolocalization and sequence analysis revealed that hTJ6 is a membrane protein with predicted six transmembrane-spanning regions, typical of ion channels, and a single putative ITAM (residues 452-466) in a juxtamembrane or hydrophobic intramembrane region. hTJ6 is highly homologous to Bos taurus 116-kDa subunit of the vacuolar proton-translocating ATPase. Over-expression of hTJ6 in HEK 293 cells increased H+ uptake into intracellular organelles, an effect that was sensitive to inhibition by bafilomycin, a selective inhibitor of vacuolar H+ pump. Northern blot analysis demonstrated three different hybridizing mRNA transcripts corresponding to 3.2, 5.0 and 7.3 kb, indicating the presence of several splice variants. Significant differences in hTJ6 mRNA levels in human tissues of different origins point to possible tissue-specific function. Although hTJ6 was found to be a poor substrate for tyrosine-phosphorylating enzymes, suggesting that its ITAM sequence is non-functional in protein tyrosine kinase-mediated signaling pathways, its role in organellar H+ pumping suggests that hTJ6 function may participate in protein trafficking/processing.
Highlights
Binding of extracellular ligands to their cognate surface receptors regulates a plethora of cell functions in a wide range of cell types
We found that anti-human TJ6 (hTJ6) antiserum immunoprecipitated a major protein band of 100 kDa from the Jurkat cell lysate, which was recognized in the immunoblot with the anti-hTJ6 antiserum (Fig. 6B). hTJ6 from resting Jurkat T cells was not phosphorylated on tyrosine residues and pervanadate induced only a weak tyrosine phosphorylation signal (Fig. 6A)
We have cloned and partially characterized the human homolog of the murine TJ6 (mTJ6) gene, termed hTJ6, which encodes a transmembrane protein containing a conserved immunoreceptor tyrosine-based activation motif (ITAM)-like sequence
Summary
Binding of extracellular ligands to their cognate surface receptors regulates a plethora of cell functions in a wide range of cell types They do so by activating receptor-linked signal transduction pathways that function as ‘on-or-off’ molecular switches, which regulate gene transcription and translation as well as post-translational processes. These signaling pathways regulate cell replication, differentiation, maturation and acquisition of specific effector functions. While differing in ligand specificity, these receptors share a stretch of amino acid sequence in their cytoplasmic tails, which is critical for the transduction of cell activation signals.
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