TULA: A novel protein that affects activation and degradation of protein tyrosine kinases

TULA (T-cell Ubiquitin Ligand) is a novel protein containing UBA and SH3 domains; and the C-terminal half contains homology to PhosphoGlycerate Mutases. TULA is the first protein described to contain both the UBA and SH3 domains. TULA is a primarily lymphoid protein, although the second protein of its family is ubiquitously present. TULA was shown to bind c-Cbl, ubiquitin and ubiquitylated proteins. As c-Cbl is an E3 ubiquitin ligase and is known to downregulate activated protein tyrosine kinases (PTKs) by ubiquitylation, involvement of TULA in this process was studied. It was found that TULA protects receptor PTKs from c-Cbl-dependant ubiquitylation driven degradation. Mice lacking TULA and the second protein of this family were viable and normal. The double knockout T cells had enhanced proliferative ability. Further analysis of these T cells showed increased tyrosine phosphorylation of Zap-70, a Syk family kinase. Therefore, TULA proteins exert an effect on PTKs but its molecular mechanism is not known. Hence, to understand these molecular mechanisms we chose to study the effect of TULA on Syk, a non-receptor PTK. Syk is found in both B and T cells, binds to c-Cbl and is ubiquitylated by c-Cbl. Our studies have shown that TULA activates Syk. However, the effect of the second protein is opposite from TULA’s effect on Syk. Therefore, in contrast to knockout data, which suggest that both the members of this family have similar/overlapping effects, our studies show that these proteins may have different effects and act through different functional mechanisms. [NIH Grant, Dept. funds]