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
| Autor: | Atsushi Wakita, Shigeru Kusumoto, Masaki Ri, Masakazu Nitta, Hirokazu Komatsu, Asahi Ito, Ryuzo Ueda, Jianmin Ding, Takashi Ishida, Fumiko Mori, Hiroki Yano, Shinsuke Iida, Atsushi Inagaki |
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| Rok vydání: | 2009 |
| Předmět: |
Immunology
Mutant Mutation Missense Biology medicine.disease_cause Biochemistry medicine Animals Humans Receptor Gene Thrombopoietin chemistry.chemical_classification Thrombopoietin receptor Mutation Genetic Diseases Inborn Cell Biology Hematology Protein Structure Tertiary Amino acid Cell biology Transmembrane domain Amino Acid Substitution chemistry Protein Multimerization Receptors Thrombopoietin Signal Transduction Thrombocythemia Essential |
| Zdroj: | Blood. 114:3325-3328 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2008-04-149047 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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