Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling
Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling
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DOI：
10.1073/pnas.1319665110
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发表时间：
2013-12-17
影响因子：
11.1
通讯作者：
Pawson, Tony
中科院分区：
文献类型：
--
作者：
Louria-Hayon, Igal;Frelin, Catherine;Pawson, Tony
LNK(Sh2b3)接头蛋白通过抑制JAK2信号通路抑制造血干细胞和祖细胞(HSPC)对多种细胞因子的反应。结果，LNK(-/-)小鼠出现造血性增生，发展为类似于骨髓增生性肿瘤非急性期的表型。此外，在人类骨髓增殖性肿瘤和急性白血病中也发现了LNK突变。我们发现LNK抑制辐射诱导的小鼠急性B细胞恶性肿瘤的发展。缺乏LNK的HSPC比野生型HSPC更有效地从辐射中恢复，这种LNK(-/-)HSPC对辐射的抵抗力是随后出现白血病的基础。对辐射抵抗机制的研究发现，细胞因子IL-11对LNK(-/-)HSPC从辐射中恢复并随后成为白血病的能力至关重要。在IL-11信号转导中，野生型LNK抑制了含Src同源区2结构域的磷酸酶-2/蛋白酪氨酸磷酸酶非受体11的酪氨酸磷酸化及其与生长因子受体结合蛋白2的关系，以及ERK MAP激酶通路的激活。事实上，含有Src同源区域2结构域的磷酸酶-2具有LNK Src同源2结构域的结合基序，该基序在IL-11刺激下被磷酸化。因此，IL-11驱动了一条增强HSPC辐射抗性和辐射诱导的B细胞恶性肿瘤的途径，但通常会被抑制性适配器LNK减弱。
The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors (HSPCs) to a variety of cytokines by inhibiting JAK2 signaling. As a consequence, Lnk(-/-) mice develop hematopoietic hyperplasia, which progresses to a phenotype resembling the nonacute phase of myeloproliferative neoplasm. In addition, Lnk mutations have been identified in human myeloproliferative neoplasms and acute leukemia. We find that Lnk suppresses the development of radiation-induced acute B-cell malignancies in mice. Lnk-deficient HSPCs recover more effectively from irradiation than their wild-type counterparts, and this resistance of Lnk(-/-) HSPCs to radiation underlies the subsequent emergence of leukemia. A search for the mechanism responsible for radiation resistance identified the cytokine IL-11 as being critical for the ability of Lnk(-/-) HSPCs to recover from irradiation and subsequently become leukemic. In IL-11 signaling, wild-type Lnk suppresses tyrosine phosphorylation of the Src homology region 2 domain-containing phosphatase-2/protein tyrosine phosphatase nonreceptor type 11 and its association with the growth factor receptor-bound protein 2, as well as activation of the Erk MAP kinase pathway. Indeed, Src homology region 2 domain-containing phosphatase-2 has a binding motif for the Lnk Src Homology 2 domain that is phosphorylated in response to IL-11 stimulation. IL-11 therefore drives a pathway that enhances HSPC radioresistance and radiation-induced B-cell malignancies, but is normally attenuated by the inhibitory adaptor Lnk.