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Blood, 8 October 2009, Vol. 114, No. 15, pp. 3325-3328. Prepublished online as a Blood First Edition Paper on May 29, 2009; DOI 10.1182/blood-2008-04-149047. This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: blood-2008-04-149047v1 114/15/3325    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 Google Scholar Articles by Ding, J. Articles by Ueda, R. PubMed PubMed Citation Articles by Ding, J. Articles by Ueda, R. Related Collections Hematopoiesis and Stem Cells Platelets and Thrombopoiesis Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLATELETS AND THROMBOPOIESIS Brief report The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity Jianmin Ding1, Hirokazu Komatsu1, Shinsuke Iida1, Hiroki Yano1, Shigeru Kusumoto1, Atsushi Inagaki1, Fumiko Mori1, Masaki Ri1, Asahi Ito1, Atsushi Wakita2, Takashi Ishida1, Masakazu Nitta3, and Ryuzo Ueda1 1 Department of Medical Oncology and Immunology, Graduate School of Medical Sciences, Nagoya City University, Nagoya; 2 Higashi Municipal Hospital of Nagoya City University, Nagoya; and 3 Department of Internal Medicine, Division of Hematology, Aichi Medical University, Aichi, Japan We previously reported that a dominant-positive activating mutation (Asn505) in the transmembrane domain (TMD) of c-MPL, which encodes the thrombopoietin receptor, caused familial essential thrombocythemia. Here, we show that the Asn505 mutation induces both autonomous dimerization of c-Mpl and signal activation in the absence of its ligand. Signal activation was preserved in a truncated mutant of Asn505 that lacked the extracellular domain of c-MPL. We also found that the substitution of the amino acid (AA) residue at position 505 with others of strong polarity (Glu, Asp, or Gln) also resulted in activated dimerization without ligand stimulation. Overall, these data show that the Asn505 mutation transduced the signal through the autonomous dimerization of the c-MPL protein due to strong AA polarity. This finding provides a new insight into the mechanism of disease causation by mutations in the TMD of cytokine/hematopoietic receptors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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