Abstract
The cross-talk of ubiquitination with other types of posttranscriptional modifications, such as phosphorylation, regulates the stability of many proteins. 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. Here we report that genetic ablation of c-Abl accelerated c-Jun degradation. Phosphorylation of the tyrosine within the PPXY motif by c-Abl inhibited c-Jun ubiquitination and its binding by Itch. The nuclear localization of c-Abl, triggered by T-cell activation signals, was essential for its activity in regulating c-Jun transcription activity. These findings define a potential molecular mechanism for the immunodeficiency in mice lacking the c-abl gene.
Highlights
Is a substrate for phosphorylation by the tyrosine kinase c-Abl [8]
The c-Abl protein is comprised of multiple domains including Src homology (SH) 3, SH2, and SH1 domains, proline-rich sequences that bind SH3-containing molecules, nuclear localization and export signals, and DNA and actin binding domains (10 –12)
It has been implicated that c-Abl might play a role in T-cell receptor (TCR) signaling because targeted disruption of the Abl1 gene in mice resulted in animals that had splenic and thymic atrophy and cell-autonomous lymphopenia [16, 17]
Summary
Is a substrate for phosphorylation by the tyrosine kinase c-Abl [8]. Tyrosine phosphorylation of c-Jun up-regulates the activations of both JNK and c-Abl in the nucleus. We report that phosphorylation of c-Jun at tyrosine 170 by c-Abl kinase inhibited Itch binding to c-Jun and protected c-Jun from Itch-induced ubiquitination and degradation. In MEFS lacking the gene encoding Itch, there was no detectable effect of the expression of either constitutively active or dominant negative c-Abl wild-type c-Jun ( p Ͻ 0.05).
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