The fusion proteins TEL-PDGFRbeta and FIP1L1-PDGFRalpha escape ubiquitination and degradation.

Abstract:

BACKGROUND:Chimeric oncogenes encoding constitutively active protein tyrosine kinases are associated with chronic myeloid neoplasms. TEL-PDGFRbeta (TPbeta, also called ETV6-PDGFRB) is a hybrid protein produced by the t(5;12) translocation, FIP1L1-PDGFRalpha (FPalpha) results from a deletion on chromosome 4q12 and ZNF198-FGFR1 is created by the t(8;13) translocation. These fusion proteins are found in patients with myeloid neoplasms associated with eosinophilia. Wild-type receptor tyrosine kinases are efficiently targeted for degradation upon activation, in a process that requires Cbl-mediated monoubiquitination of receptor lysines. Since protein degradation pathways have been identified as useful targets for cancer therapy, the aim of this study was to compare the degradation of hybrid and wild-type receptor tyrosine kinases. DESIGN AND METHODS:We used Ba/F3 as a model cell line, as well as leukocytes from two patients, to analyze hybrid protein degradation. RESULTS:In contrast to the corresponding wild-type receptors, which are quickly degraded upon activation, we observed that TPbeta, FPalpha and the ZNF198-FGFR1 hybrids escaped down-regulation in Ba/F3 cells. The high stability of TPbeta and FPalpha hybrid proteins was confirmed in leukocytes from leukemia patients. Ubiquitination of TPbeta and FPalpha was much reduced compared to that of wild-type receptors, despite marked Cbl phosphorylation in cells expressing hybrid receptors. The fusion of a destabilizing domain to TPbeta induced protein degradation. Instability was reverted by adding the destabilizing domain ligand, Shield1. The destabilization of this modified TPbeta reduced cell transformation and STAT5 activation. CONCLUSIONS:We have shown that chimeric receptor tyrosine kinases escape ubiquitination and down-regulation and that their stabilization is critical to efficient stimulation of cell proliferation.

journal_name

Haematologica

journal_title

Haematologica

authors

Toffalini F,Kallin A,Vandenberghe P,Pierre P,Michaux L,Cools J,Demoulin JB

doi

10.3324/haematol.2008.001149

subject

Has Abstract

pub_date

2009-08-01 00:00:00

pages

1085-93

issue

8

eissn

0390-6078

issn

1592-8721

pii

94/8/1085

journal_volume

94

pub_type

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