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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >Constitutive activation of SHP2 protein tyrosine phosphatase inhibits ICSBP-induced transcription of the gene encoding gp91PHOX during myeloid differentiation.
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Constitutive activation of SHP2 protein tyrosine phosphatase inhibits ICSBP-induced transcription of the gene encoding gp91PHOX during myeloid differentiation.

机译：SHP2蛋白酪氨酸磷酸酶的组成性激活抑制了髓系分化过程中ICSBP诱导的编码gp91PHOX的基因的转录。

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摘要

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 gp91(PHOX) (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. Since 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-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.
机译：IFN共有序列结合蛋白（ICSBP;也称为IFN调节因子8）是在髓细胞和B细胞中表达的转录因子。在以前的研究中，我们发现ICSBP激活了编码gp91（PHOX）的基因（CYBB基因）的转录，这是吞噬细胞呼吸爆发氧化酶的限速成分，仅在骨髓生成的早幼粒细胞阶段后表达。以前，我们发现CYBB转录取决于特定ICSBP酪氨酸残基的磷酸化。由于ICSBP在骨髓生成过程中被酪氨酸磷酸化，因此提供了分化阶段特异性CYBB转录的机制。在当前的研究中，我们发现ICSBP是未成熟髓细胞中而不是骨髓生成过程中含有Src同源性的酪氨酸磷酸酶2（SHP2-PTP）的底物。因此，SHP2-PTP通过去磷酸化ICSBP抑制髓样祖细胞中的CYBB转录和呼吸爆发活性。相反，我们发现ICSBP是SHP2的白血病相关的，组成型活性突变体形式的底物，如前所述，贯穿整个分化过程。与此相一致，在分化的髓样细胞中，组成型SHP2激活阻止了ICSBP诱导的CYBB转录和呼吸爆发活性。 ICSBP缺陷和组成型SHP2激活已在人类骨髓增生异常综合症中描述。由于这两种异常可能并存，因此我们的结果确定了这种恶性骨髓病中吞噬细胞功能受损的潜在分子机制。

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