title: 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.
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.
authors.affiliation: Department of Medical Oncology and Immunology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Ding
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Komatsu
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yano
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kusumoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inagaki
authors.forename: Fumiko
authors.initials: F
authors.lastname: Mori
authors.forename: Masaki
authors.initials: M
authors.lastname: Ri
authors.forename: Asahi
authors.initials: A
authors.lastname: Ito
authors.forename: Atsushi
authors.initials: A
authors.lastname: Wakita
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishida
authors.forename: Masakazu
authors.initials: M
authors.lastname: Nitta
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020125:Mutation, Missense; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013920:Thrombocythemia, Essential / Q000235:genetics / Q000378:metabolism*
chemical_list: D053628:Receptors, Thrombopoietin; C082218:MPL protein, human