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

Author:

Ding Jianmin1,Komatsu Hirokazu1,Iida Shinsuke1,Yano Hiroki1,Kusumoto Shigeru1,Inagaki Atsushi1,Mori Fumiko1,Ri Masaki1,Ito Asahi1,Wakita Atsushi2,Ishida Takashi1,Nitta Masakazu3,Ueda Ryuzo1

Affiliation:

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

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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