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Phosphorylated c-MPL tyrosine 591 regulates thrombopoietin-induced signaling

Authors
  • Sangkhae, Veena
  • Saur, Sebastian Jonas
  • Kaushansky, Alexis
  • Kaushansky, Kenneth
  • Hitchcock, Ian Stuart1, 2, 3, 4, 5
  • 1 Department of Medicine
  • 2 Stony Brook University
  • 3 Department of Hematology/Oncology
  • 4 Eberhard Karls University TÜbingen
  • 5 Seattle Biomedical Research Institute
Type
Published Article
Journal
Experimental Hematology
Publisher
Elsevier
Publication Date
Jan 01, 2014
Accepted Date
Feb 21, 2014
Identifiers
DOI: 10.1016/j.exphem.2014.02.007
Source
Elsevier
Keywords
License
Unknown

Abstract

Thrombopoietin (TPO) is the primary regulator of platelet production, affecting cell survival, proliferation and differentiation through binding to and stimulation of the cell surface receptor c-MPL. Activating mutations in c-MPL constitutively stimulate downstream signaling pathways, leading to aberrant hematopoiesis and contribute to development of myeloproliferative neoplasms. Several studies have mapped the tyrosine residues within the cytoplasmic domain of c-MPL that mediate these cellular signals; however, secondary signaling pathways are incompletely understood. In this study we focused on c-MPL tyrosine 591 (Y591). We found Y591 of wild-type c-MPL to be phosphorylated in the presence of TPO. Additionally, eliminating Y591 phosphorylation by mutation to Phe resulted in decreased total receptor phosphorylation. Using an SH2/PTB domain binding microarray, we identified novel c-MPL binding partners for phosphorylated Y591, including Src homology phosphatase-1 (SHP-1), spleen tyrosine kinase (SYK) and Bruton's tyrosine kinase (BTK). The functional significance of binding partners was determined through siRNA treatment of Ba/F3-MPL cells, confirming that the increase in pERK1/2 resulting from removal of Y591 may be mediated by SYK. These findings identify a novel negative regulatory pathway that controls TPO-mediated signaling, advancing our understanding of the mechanisms required for successful maintenance of hematopoietic stem cells and megakaryocyte development.

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