Loss of SHIP and CIS recruitment to the granulocyte colony-stimulating factor receptor contribute to hyperproliferative responses in severe congenital neutropenia/acute myelogenous leukemia
Loss of SHIP and CIS recruitment to the granulocyte colony-stimulating factor receptor contribute to hyperproliferative responses in severe congenital neutropenia/acute myelogenous leukemia
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DOI：
10.4049/jimmunol.173.8.5036
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发表时间：
2004-10-15
影响因子：
4.4
通讯作者：
Avalos, BR
中科院分区：
文献类型：
--
作者：
Hunter, MG;Jacob, A;Avalos, BR
在患有严重先天性中性粒细胞减少症（SCN）的患者中，G-CSF受体（G-CSFR）的突变被假定有助于转化为急性髓性白血病（AML）。这些突变导致受体内化缺陷和持续的细胞活化，表明G-CSFR的负信号丢失。在本文中，我们研究了SHIP和丝氨酸诱导的Src同源2蛋白（CIS）在下调G-CSFR信号中的作用，并证明受体突变导致的招募损失导致异常信号传导。我们发现SHIP与G-CSFR中Tyr（744）和Tyr（764）对应的磷酸肽结合，Tyr（764）是SHIP体内磷酸化和SHIP/Shc复合物形成所必需的。表达缺乏Tyr（764）的G-CSFR形式的细胞表现出对G-CSF的超敏反应和增强的增殖，但程度低于SCN/AML患者中最常见的突变G-CSFR形式，这促使我们研究细胞因子信号传导蛋白的抑制因子是否也下调G-CSFR信号。发现G-CSF诱导CIS和与对应于G-CSFR的Tyr（729）和Tyr（744）的磷酸肽结合的CIS的表达。在具有缺乏Tyr（729）和Tyr（744）的SCN/AML突变体G-CSFR的细胞中，CIS的表达延长，这也与G-CSFR表达增加相关。这些发现表明，SHIP和CIS与G-CSFR中的远端磷酸酪氨酸残基相互作用，分别通过限制增殖和调节G-CSFR的表面表达来负调节G-CSFR信号传导。靶向限制G-CSFR信号传导的抑制途径的新治疗方法可能在治疗SCN/AML患者中具有前景。
Mutations in the G-CSF receptor (G-CSFR) in patients with severe congenital neutropenia (SCN) are postulated to contribute to transformation to acute myelogenous leukemia (AML). These mutations result in defective receptor internalization and sustained cellular activation, suggesting a loss of negative signaling by the G-CSFR. In this paper we investigated the roles of SHIP and cytokine-inducible Src homology 2 protein (CIS) in down-modulating G-CSFR signals and demonstrate that loss of their recruitment as a consequence of receptor mutations leads to aberrant signaling. We show that SHIP binds to phosphopeptides corresponding to Tyr(744) and Tyr(764) in the G-CSFR and that Tyr(764) is required for in vivo phosphorylation of SHIP and the formation of SHIP/Shc complexes. Cells expressing a G-CSFR form lacking Tyr(764) exhibited hypersensitivity to G-CSF and enhanced proliferation, but to a lesser degree than observed with the most common mutant G-CSFR form in patients with SCN/AML, prompting us to investigate whether suppressor of cytokine signaling proteins also down-modulate G-CSFR signals. G-CSF was found to induce the expression of CIS and of CIS bound to phosphopeptides corresponding to Tyr(729) and Tyr(744) of the G-CSFR. The expression of CIS was prolonged in cells with the SCN/AML mutant G-CSFR lacking Tyr(729) and Tyr(744), which also correlated with increased G-CSFR expression. These findings suggest that SHIP and CIS interact with distal phosphotyrosine residues in the G-CSFR to negatively regulate G-CSFR signaling by limiting proliferation and modulating surface expression of the G-CSFR, respectively. Novel therapeutic approaches targeting inhibitory pathways that limit G-CSFR signaling may have promise in the treatment of patients with SCN/AML.