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首页> 外文期刊>Oncogene >Regulation of mixed lineage kinase 3 is required for Neurofibromatosis-2-mediated growth suppression in human cancer
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Regulation of mixed lineage kinase 3 is required for Neurofibromatosis-2-mediated growth suppression in human cancer

机译：调节混合谱系激酶3是神经纤维瘤病2介导的人类癌症生长抑制所必需的

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摘要

The Neurofibromatosis-2 (NF2 ) tumor suppressor merlin negatively regulates cell proliferation in numerous cell types. We have previously shown that the NF2 protein (merlin/schwannomin) associates with mixed lineage kinase 3 (MLK3), a mitogen-activated protein kinase (MAPK) kinase kinase that is required for the proliferation of normal and neoplastic cells. In this study, we show that merlin inhibits MLK3 activity, as well as the activation of its downstream effectors, B-Raf, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). The ability of merlin to regulate MLK3 activity requires a direct association between MLK3 and residues in the C-terminal region of merlin. Merlin integrates Rho GTPase family signaling with MAPK activity by inhibiting the binding between MLK3 and its upstream activator, Cdc42. Furthermore, we demonstrate that MLK3 is required for merlin-mediated suppression of cell proliferation and invasion. Collectively, these results establish merlin as a potent inhibitor of MLK3, ERK and JNK activation in cancer, and provide a mechanistic link between deregulated MAPK and Rho GTPase signaling in NF2 growth control.
机译：Neurofibromatosis-2（NF2）肿瘤抑制因子Merlin在许多细胞类型中均负调控细胞增殖。先前我们已经证明NF2蛋白（merlin / schwannomin）与混合谱系激酶3（MLK3）相关联，MLK3是正常和赘生性细胞增殖所必需的有丝分裂原活化蛋白激酶（MAPK）激酶激酶。在这项研究中，我们表明merlin抑制MLK3活性，以及​​其下游效应子B-Raf，细胞外信号调节激酶（ERK）和c-Jun N端激酶（JNK）的激活。 merlin调节MLK3活性的能力要求MLK3和merlin C端区域的残基之间直接缔合。 Merlin通过抑制MLK3及其上游激活因子Cdc42之间的结合，将Rho GTPase家族信号转导与MAPK活性整合在一起。此外，我们证明MLK3是merlin介导的细胞增殖和侵袭抑制所必需的。总的来说，这些结果确立了梅林作为癌症中MLK3，ERK和JNK活化的有效抑制剂，并在NF 2生长控制中的失调的MAPK和Rho GTPase信号传导之间提供了机理联系。

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