A thrombopoietin receptor mutant deficient in Jak-STAT activation mediates proliferation but not differentiation in UT-7 cells

Marion Dorsch, Nika N. Danial, Paul B Rothman, Stephen P. Goff

Research output: Contribution to journalArticle

Abstract

Thrombopoietin (TPO) stimulates proliferation and differentiation of cells of the megakaryocytic lineage. It exerts its function by binding and activating c-mpl, a member of the hematopoietic receptor superfamily. Upon binding of TPO to its receptor, numerous signaling events are triggered. These include activation of the Jak-STAT (signal transducers and activators of transcription) pathway, mitogen-activated protein kinase (MAPK), Tec, and phospatidylinositol (PI) 3-kinase and phosphorylation of Shc and Vav. The contribution of different signaling pathways to the induction of specific cellular processes such as proliferation and differentiation is incompletely understood. We have previously described a mutant of c-mpl that fails to activate the Jak-STAT pathway but nevertheless retains its ability to mediate proliferation and activation of most signaling events in the murine hematopoietic precursor cell lines BAF/3 and 32D. We confirm here the ability of this mutant to mediate proliferation in the absence of Jak-STAT activation in the human cell line UT-7 and further show that this mutant fails to mediate TPO-induced megakaryocytic differentiation. Comparison of the signaling capacity of this mutant in UT-7 and BAF/3 cells shows considerable cell-type-specific differences. Whereas in BAF/3 cells the mutant still mediates activation of Sho, MAPK, Vav, and PI 3-kinase at levels comparable to the wild-type receptor, these events are strongly diminished in UT-7 cells expressing the mutant. Furthermore, we show that the C-terminal 25 amino acid residues of the receptor mutant are crucial for the mitogenic response in UT- 7 cells.

Original languageEnglish (US)
Pages (from-to)2676-2685
Number of pages10
JournalBlood
Volume94
Issue number8
StatePublished - Oct 15 1999
Externally publishedYes

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Thrombopoietin Receptors
Thrombopoietin
Chemical activation
Cells
Mitogen-Activated Protein Kinases
Phosphotransferases
Phosphorylation
Amino Acid Receptors
Transcription
Cell Line
Cell Lineage
Transducers
Amino Acids

ASJC Scopus subject areas

  • Hematology

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A thrombopoietin receptor mutant deficient in Jak-STAT activation mediates proliferation but not differentiation in UT-7 cells. / Dorsch, Marion; Danial, Nika N.; Rothman, Paul B; Goff, Stephen P.

In: Blood, Vol. 94, No. 8, 15.10.1999, p. 2676-2685.

Research output: Contribution to journalArticle

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AU - Goff, Stephen P.

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