Accuri C6 Flow Cytometer System
A more recent version of this article appeared on March 1, 2008

Published online before print December 18, 2007
This Article
Right arrow Full Text (Reprint (PDF))
Right arrow All Versions of this Article:
jlb.0807514v1
83/3/680    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhu, C.
Right arrow Articles by Eklund, E. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhu, C.
Right arrow Articles by Eklund, E. A.
© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0807514

Received for publication August 2, 2007.
Revised November 15, 2007.
Accepted for publication November 16, 2007.

Article

Constitutive activation of SHP2 protein tyrosine phosphatase inhibits ICSBP-induced transcription of the gene encoding gp91PHOX during myeloid differentiation

Chunliu Zhu *, Stephan Lindsey *, Iwonna Konieczna *, and Elizabeth A. Eklund *{dagger}@

*The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; and {dagger}Jesse Brown Veterans Health Administration Medical Center, Chicago, Illinois, USA

@ To whom correspondence should be addressed. E-mail: e-eklund{at}northwestern.edu.


arrow
Abstract

The IFN consensus sequence-binding protein (ICSBP; also referred to as IFN regulatory factor 8) is a transcription factor, which is expressed in myeloid and B cells. In previous studies, we found that ICSBP activated transcription of the gene encoding gp91PHOX (the CYBB gene), a rate-limiting component of the phagocyte respiratory burst oxidase, expressed exclusively after the promyelocyte stage of myelopoiesis. Previously, we found that CYBB transcription was dependent on phosphorylation of specific ICSBP tyrosine residues. As ICSBP is tyrosine-phosphorylated during myelopoiesis, this provided a mechanism of differentiation stage-specific CYBB transcription. In the current studies, we found that ICSBP was a substrate for Src homology-containing tyrosine phosphatase 2 (SHP2) protein-tyrosine-phosphatase (PTP) in immature myeloid cells but not during myelopoiesis. Therefore, SHP2-PTP inhibited CYBB transcription and respiratory burst activity in myeloid progenitor cells by dephosphorylating ICSBP. In contrast, we found that ICSBP was a substrate for a leukemia-associated, constitutively active mutant form of SHP2, described previously, throughout differentiation. Consistent with this, constitutive SHP2 activation blocked ICSBP-induced CYBB transcription and respiratory burst activity in differentiating myeloid cells. ICSBP-deficiency and constitutive SHP2 activation have been described in human myelodysplastic syndromes. As these two abnormalities may coexist, our results identified a potential molecular mechanism for impaired phagocyte function in this malignant myeloid disease.

Key Words: IFN consensus sequence-binding protein • respiratory burst oxidase • gene regulation