The anti-apoptotic form of tyrosine kinase Lyn that is generated by proteolysis is degraded by the N-end rule pathway

作者：Eldeeb Mohamed A; Fahlman Richard P^*

来源：Oncotarget, 2014, 5(9): 2714-2722.

DOI：10.18632/oncotarget.1931

• Lyn
• N-end rule
• ubiquitination
• protein degradation
• UBR

The activation of apoptotic pathways results in the caspase cleavage of the Lyn tyrosine kinase to generate the N-terminal truncated Lyn Delta N. This Lyn Delta N fragment has been demonstrated to exert negative feedback on imatinib induced apoptosis in chronic myelogenous leukemia (CML) K562 cells. Our investigations focus on Lyn Delta N stability and how reduced stability reduces imatinib resistance. As the proteolytical generated Lyn Delta N has a leucine as an N-terminal amino acid, we hypothesized that Lyn Delta N would be degraded by the N-end rule pathway. We demonstrated that Lyn Delta N is unstable and that its stability is dependent on the identity of its N-terminus. Additionally we established that Lyn Delta N degradation could be inhibited by either inhibiting the proteasome or knocking down the UBR1 and UBR2 ubiquitin E3 ligases. Importantly, we also demonstrate that Lyn Delta N degradation by the N-end rule counters the imatinib resistance of K562 cells provided by Lyn Delta N expression. Together our data suggest a possible mechanism for the N-end rule pathway having a link to imatinib resistance in CML. With Lyn Delta N being an N-end rule substrate, it provides the first example that this pathway can also provide a pro-apoptotic function as previous reports have currently only demonstrated anti-apoptotic roles for the N-end rule pathway.

• 出版日期2014-5