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Blood, 15 September 2008, Vol. 112, No. 6, pp. 2222-2231. Prepublished online as a Blood First Edition Paper on May 16, 2008; DOI 10.1182/blood-2008-01-134049. This Article Full Text (PDF) All Versions of this Article: blood-2008-01-134049v1 112/6/2222    most recent Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hitchcock, I. S Articles by Kaushansky, K. Search for Related Content PubMed PubMed Citation Articles by Hitchcock, I. S Articles by Kaushansky, K. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 15, 2008 Accepted April 29, 2008 YRRL motifs in the cytoplasmic domain of the thrombopoietin receptor regulate receptor internalization and degradation Ian S Hitchcock*, Maximus M Chen, Jennifer R King, and Kenneth Kaushansky Department of Medicine, University of California San Diego, La Jolla, CA, United States * Corresponding author; email: ihitchcock{at}ucsd.edu. Thrombopoietin (Tpo), acting through the c-Mpl receptor, promotes the survival and proliferation of hematopoietic stem and progenitor cells and drives megakaryocyte differentiation. The pro-proliferation and survival signals activated by Tpo must therefore be tightly regulated to prevent uncontrolled cell growth. In this work we determined the mechanisms that control Tpo-stimulated c-Mpl internalization and defined the processes leading to its degradation. Stimulation of BaF-Mpl cells with Tpo leads to rapid, clathrin-dependent endocytosis of the receptor. Using small interfering (si)RNA we found that inhibition of adaptor protein 2 (AP2), which mediates endocytosis of transmembrane proteins, strongly attenuates Tpo-stimulated c-Mpl internalization. AP2 interacts with YXX motifs and we identified 2 such motifs in c-Mpl (Y8RRL and Y78RRL) and investigated Tpo-stimulated internalization of receptors bearing point mutations at these sites. After Tpo stimulation, internalization was greatly reduced in c-Mpl Y78F and c-Mpl Y8+78F and these cell lines also exhibited increased proliferation and increased strength and duration of Jak2, STAT5, AKT, and ERK1/2 activation in response to Tpo. We also found that the Y8RRL motif regulates Tpo-stimulated lysosomal degradation of c-Mpl. Our data establishes that c-Mpl cytoplasmic YRRL motifs are responsible for both Tpo-mediated internalization via interactions with AP2 and lysosomal targeting following endocytosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: TPO signaling: when the tyrosines go marching in(side) Roberto Pozner and Mirta Schattner Blood 2008 112: 2171-2172. [Full Text] [PDF] This article has been cited by other articles: V. S. Subramanian, J. S. Marchant, M. J. Boulware, T. Y. Ma, and H. M. Said Membrane targeting and intracellular trafficking of the human sodium-dependent multivitamin transporter in polarized epithelial cells Am J Physiol Cell Physiol, April 1, 2009; 296(4): C663 - C671. [Abstract] [Full Text] [PDF]

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