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Blood, 21 May 2009, Vol. 113, No. 21, pp. 5287-5297. Prepublished online as a Blood First Edition Paper on March 31, 2009; DOI 10.1182/blood-2008-09-179572. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-09-179572v1 113/21/5287    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sulahian, R. Articles by Huang, L. J.-s. Search for Related Content PubMed PubMed Citation Articles by Sulahian, R. Articles by Huang, L. J.-s. Related Collections Hematopoiesis and Stem Cells Red Cells, Iron, and Erythropoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS, IRON, AND ERYTHROPOIESIS Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia Rita Sulahian1, Ondine Cleaver2, and Lily Jun-shen Huang1 Departments of 1 Cell Biology and 2 Molecular Biology, University of Texas Southwestern Medical Center at Dallas Epo-induced endocytosis of EpoR plays important roles in the down-regulation of EpoR signaling and is the primary means that regulates circulating Epo concentrations. Here we show that cell-surface EpoR is internalized via clathrin-mediated endocytosis. Both JAK2 kinase activity and EpoR cytoplasmic tyrosines are important for ligand-dependent EpoR internalization. Phosphorylated Y429, Y431, and Y479 in the EpoR cytoplasmic domain bind p85 subunit of PI3 kinase on Epo stimulation and individually are sufficient to mediate Epo-dependent EpoR internalization. Knockdown of p85 and p85β or expression of their dominant-negative forms, but not inhibition of PI3 kinase activity, dramatically impaired EpoR internalization, indicating that p85 and p85β may recruit proteins in the endocytic machinery on Epo stimulation. Furthermore, mutated EpoRs from primary familial and congenital polycythemia (PFCP) patients lacking the 3 important tyrosines do not bind p85 or internalize on stimulation. Addition of residues encompassing Y429 and Y431 to these truncated receptors restored p85β binding and Epo sensitivity. Our results identify a novel PI3 kinase activity-independent function of p85 in EpoR internalization and support a model that defects of internalization in truncated EpoRs from PFCP patients contribute to Epo hypersensitivity and prolonged signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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