PSTPIP2 dysregulation contributes to aberrant terminal differentiation in GATA-1-deficient megakaryocytes by activating LYN.
PSTPIP2 dysregulation contributes to aberrant terminal differentiation in GATA-1-deficient megakaryocytes by activating LYN.
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PSTPIP2 失调通过激活 LYN 导致 GATA-1 缺陷型巨核细胞异常终末分化
DOI：
10.1038/cddis.2013.512
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发表时间：
2014-01-09
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
GATA1 突变与唐氏综合症儿童的短暂性骨髓增殖性疾病 (TMD) 和急性巨核细胞白血病 (AMKL) 密切相关。 GATA-1缺陷型巨核细胞中的许多基因发生改变，这可能导致这些恶性细胞的过度增殖和异常终末分化。在这项研究中，我们证明 Pstpip2 是一种控制巨核细胞生成的 GATA-1 抑制基因。 PSTPIP2 的异位表达损害了巨核细胞的分化，K562 细胞中 CD41 表达的减少和 DNA 含量的减少证明了这一点。 PSTPIP2 过度表达还导致 Src 家族激酶激活增强，随后 ERK 磷酸化减少。一致的是，PSTPIP2 敲低对分化和信号转导显示出相反的影响。此外，PSTPIP2的W232A突变体与PEST家族磷酸酶相互作用存在缺陷，PEST家族磷酸酶招募c-Src末端激酶（CSK）来抑制Src家族激酶，因此无法抑制分化并失去增强Src家族激酶或减少ERK磷酸化的能力。事实上，PSTPIP2的W232A突变体促进了巨核细胞的分化。这些观察结果表明，PSTPIP2 招募 PEST 磷酸酶以某种方式阻断 CSK 活性，导致 Src 家族激酶激活增强并减少 ERK 磷酸化，最终抑制巨核细胞分化。支持这一观点的是，PSTPIP2 与 LYN 相互作用，显性失活 LYN (LYN DN) 的表达压倒了 PSTPIP2 对分化和 ERK 信号传导的抑制作用。此外，组成型活性 LYN (LYN CA) 使 PSTPIP2 敲低细胞中增强的巨核细胞分化正常化并抑制 ERK 信号传导。最后，我们发现 PSTPIP2 抑制 ERK 信号传导、分化和增殖，并证实 PSTPIP2 上调抑制原代小鼠骨髓细胞中巨核细胞的发育。因此，我们的研究揭示了一种新机制，GATA-1缺陷导致的PSTPIP2失调可能导致相关疾病发病机制中异常巨核细胞增殖和分化。
GATA1 mutations are tightly associated with transient myeloproliferative disorder (TMD) and acute megakaryoblstic leukemia (AMKL) in children with Down syndrome. Numerous genes are altered in GATA-1-deficient megakaryocytes, which may contribute to the hyperproliferation and abnormal terminal differentiation of these malignant cells. In this study, we demonstrate that Pstpip2 is a GATA-1-repressed gene that controls megakaryopoiesis. Ectopic expression of PSTPIP2 impaired megakaryocytic differentiation as evidenced by a decrease of CD41 expression and reduced DNA content in K562 cells. PSTPIP2 overexpression also caused enhanced activation of Src family kinases and subsequently reduced ERK phosphorylation. Consistently, PSTPIP2 knockdown showed the opposite effect on differentiation and signaling. Moreover, the W232A mutant of PSTPIP2, defective in its interaction with PEST family phosphatases that recruit c-Src terminal kinase (CSK) to suppress Src family kinases, failed to inhibit differentiation and lost its ability to enhance Src family kinases or reduce ERK phosphorylation. In fact, the W232A mutant of PSTPIP2 promoted megakaryocyte differentiation. These observations suggest that PSTPIP2 recruiting PEST phosphatases somehow blocked CSK activity and led to enhanced activation of Src family kinases and reduced ERK phosphorylation, which ultimately repressed megakaryocyte differentiation. Supporting this idea, PSTPIP2 interacted with LYN and the expression of a dominant negative LYN (LYN DN) overwhelmed the inhibitory effect of PSTPIP2 on differentiation and ERK signaling. In addition, a constitutively active LYN (LYN CA) normalized the enhanced megakaryocyte differentiation and repressed ERK signaling in PSTPIP2 knockdown cells. Finally, we found that PSTPIP2 repressed ERK signaling, differentiation, and proliferation and verified that PSTPIP2 upregulation repressed megakaryocyte development in primary mouse bone marrow cells. Our study thus reveals a novel mechanism by which dysregulation of PSTPIP2 due to GATA-1 deficiency may contribute to abnormal megakaryocyte proliferation and differentiation in pathogenesis of related diseases.
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影响因子：
64.5
作者：
Levinson NM;Seeliger MA;Cole PA;Kuriyan J
通讯作者：
Kuriyan J
影响因子：
50.3
作者：
Chen E;Beer PA;Godfrey AL;Ortmann CA;Li J;Costa-Pereira AP;Ingle CE;Dermitzakis ET;Campbell PJ;Green AR
通讯作者：
Green AR
影响因子：
20.3
作者：
Grosse, J;Chitu, V;Stanley, ER
通讯作者：
Stanley, ER
DOI：
10.1084/jem.183.2.651
发表时间：
1996-02-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
de Sauvage FJ;Carver-Moore K;Luoh SM;Ryan A;Dowd M;Eaton DL;Moore MW
通讯作者：
Moore MW
影响因子：
20.3
作者：
Chitu, Violeta;Ferguson, Polly J.;Stanley, E. Richard
通讯作者：
Stanley, E. Richard