Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Blood. 2010 Feb 11;115(6):1254-63. doi: 10.1182/blood-2009-06-227033. Epub 2009 Oct 30.

Ubiquitination and degradation of the thrombopoietin receptor c-Mpl.

Author information

  • 1Department of Medicine, University of California San Diego, La Jolla, CA, USA.

Abstract

Regulation of growth factor and cytokine signaling is essential for maintaining physiologic numbers of circulating hematopoietic cells. Thrombopoietin (Tpo), acting through its receptor c-Mpl, is required for hematopoietic stem cell maintenance and megakaryopoiesis. Therefore, the negative regulation of Tpo signaling is critical in many aspects of hematopoiesis. In this study, we determine the mechanisms of c-Mpl degradation in the negative regulation of Tpo signaling. We found that, after Tpo stimulation, c-Mpl is degraded by both the lysosomal and proteasomal pathways and c-Mpl is rapidly ubiquitinated. Using site-directed mutagenesis, we were able to determine that c-Mpl is ubiquitinated on both of its intracellular lysine (K) residues (K(553) and K(573)). By mutating these residues to arginine, ubiquitination and degradation were significantly reduced and caused hyperproliferation in cell lines expressing these mutated receptors. Using short interfering RNA and dominant negative overexpression, we also found that c-Cbl, which is activated by Tpo, acts as an E3 ubiquitin ligase in the ubiquitination of c-Mpl. Our findings identify a previously unknown negative regulatory pathway for Tpo signaling that may significantly impact our understanding of the mechanisms affecting the growth and differentiation of hematopoietic stem cells and megakaryocytes.

Comment in

PMID:
19880496
[PubMed - indexed for MEDLINE]
PMCID:
PMC2826235
Free PMC Article

Images from this publication.See all images (6)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk