Functional analysis of the cytoplasmic domain of the human Mpl receptor for tyrosine-phosphorylation of the signaling molecules, proliferation and differentiation

Haruhiko Morita, Tomoyuki Tahara, Atsushi Matsumoto, Takashi Kato, Hiroshi Miyazaki, Hideya Ohashi

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Abstract

To investigate the functional domains for signal transduction of human Mpl, we constructed a series of human c-mpl cDNAs with various deletions in the cytoplasmic domain, and then introduced each cDNA into murine IL3-dependent myeloid leukemia FDC/P2 cells to establish stable transformants. We examined the growth and differentiation responses and tyrosine phosphorylation of the intracellular signaling proteins including Jak2, Tyk2, Stat3, Stat5, Vav, SHPTP2, Cbl, Shc and Shc-associated p145 when receptor stimulation occurred after thrombopoietin (TPO) binding. TPO stimulated cell proliferation and induced the expression of megakaryocyte lineage-specific AP-51 and CD61 cell surface antigens and tyrosine phosphorylation of the signaling proteins in transformants expressing full length human Mpl. These results suggested that Mpl not only induced proliferation but also transduced megakaryocyte-specific differentiation signals into FDC/P2 cells. Mutational analysis of human Mpl indicated that the N-terminal region of its cytoplasmic domain is necessary and sufficient to transduce proliferation and differentiation signals into cells, while the C-terminal region may also play important roles in transducing the differentiation signals.

Original languageEnglish
Pages (from-to)228-234
Number of pages7
JournalFEBS Letters
Volume395
Issue number2-3
DOIs
Publication statusPublished - 1996 Oct 21

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Keywords

  • Differentiation
  • Mpl
  • Proliferation
  • Signal transduction
  • Thrombopoietin

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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