The membrane-proximal region of the thrombopoietin receptor confers its high surface expression by JAK2-dependent and -independent mechanisms

Wei Tong, Rita Sulahian, Alec W. Gross, Natalie Hendon, Harvey F. Lodish, Lily Jun Shen Huang

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Janus tyrosine kinase 2 (JAK2) is essential for signaling by the thrombopoietin (TpoR) and erythropoietin (EpoR) receptors. In the absence of JAK2 most EpoR molecules are retained in the endoplasmic reticulum in an Endo H-sensitive form. In contrast, we show that in the absence of JAK2 a large fraction of the TpoR is processed to the mature Endo H-resistant form and reaches the cell surface. By studying chimeras of the TpoR and EpoR we show that high surface expression of the TpoR is entirely conferred by the membrane-proximal region of the intracellular domain that includes the juxtamembrane, Box 1, and Box 2 regions. The TpoR intracellular domain shows similar effects on receptor endocytosis rate as that of the EpoR, but does stabilize the mature receptor isoform from degradation. Co-expression of JAK2 further stabilizes mature TpoR and thus further increases its surface expression. This JAK2 effect depends on the Box 1 region, the only JAK2 interacting site in the TpoR. By contrast, EpoR requires Box 1 as well as the flanking 20 residues on the C-terminal side for JAK2 interaction and JAK2-dependent surface expression. Our study suggests that whereas cell surface expression of type I cytokine receptors requires their cognate JAKs, the mechanisms governing receptor-JAK interactions differ among receptors interacting with the same JAK protein.

Original languageEnglish (US)
Pages (from-to)38930-38940
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number50
DOIs
StatePublished - Dec 15 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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