Lochab S, Pal P, Kapoor I, Kanaujiya JK, Sanyal S, Behre G, Trivedi AK

Tight control between activation and attenuation of G-CSFR signaling is essential to regulate survival, proliferation and differentiation of myeloid progenitor cells. Previous studies demonstrated negative regulation of G-CSFR through endosomal-lysosomal routing and ubiquitin-proteasome mediated degradation. However, very few E3 ubiquitin ligases are known to target G-CSFR for ubiquitin proteasome pathway. ...

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Here we identified Fbw7, a substrate recognizing component of SCF ubiquitin ligase physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation. Our data shows that Fbw7 also interacts with and degrades G-CSFR-T718 (a truncated mutant of G-CSFR found in SCN/AML patients) though at a quite slower rate compared to G-CSFR. We further show that GSK3β, like Fbw7 also targets G-CSFR and G-CSFR-T718 for degradation; however, Fbw7 and GSK3β are interdependent to target G-CSFR/G-CSFR-T718 for degradation because they are unable to degrade G-CSFR individually when either of them are knocked down. We further show that Fbw7 mediated downregulation of G-CSFR inhibits STAT3 phosphorylation which is required for G-CSF dependent granulocytic differentiation. In addition, our data also shows that inhibition of Fbw7 restores G-CSFR signaling leading to enhanced STAT3 activity resulting in massive granulocytic differentiation. These data indicate that Fbw7 together with GSK3β negatively regulates G-CSFR expression and its downstream signaling.

Date: Jun. 29, 2013

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