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首页> 外文期刊>The FEBS journal >Identification of mitogen-activated protein/extracellular signal-responsive kinase kinase 2 as a novel partner of the scaffolding protein human homolog of disc-large
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Identification of mitogen-activated protein/extracellular signal-responsive kinase kinase 2 as a novel partner of the scaffolding protein human homolog of disc-large

机译：鉴定有丝分裂原活化蛋白/细胞外信号响应激酶激酶2为大盘支架蛋白人同源物的新型伴侣

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Human disc-large homolog (hDlg), also known as synapse-associated protein 97, is a scaffold protein, a member of the membrane-associated guanylate kinase family, implicated in neuronal synapses and epithelial-epithelial cell junctions whose expression and function remains poorly characterized in most tissues, particularly in the vasculature. In human vascular tissues, hDlg is highly expressed in smooth muscle cells (VSMCs). Using the yeast two-hybrid system to screen a human aorta cDNA library, we identified mitogen-activated protein/extracellular signal-responsive kinase (ERK) kinase (MEK) 2, a member of the ERK cascade, as an hDlg binding partner. Site-directed mutagenesis showed a major involvement of the PSD-95, disc-large, ZO-1 domain-2 of hDlg and the C-terminal sequence RTAV of MEK2 in this interaction. Coimmunoprecipitation assays in both human VSMCs and human embryonic kidney 293 cells, demonstrated that endogenous hDlg physically interacts with MEK2 but not with MEK1. Confocal microscopy suggested a colocalization of the two proteins at the inner layer of the plasma membrane of confluent human embryonic kidney 293 cells, and in a perinuclear area in human VSMCs. Additionally, hDlg also associates with the endoplasmic reticulum and microtubules in these latter cells. Taken together, these findings allow us to hypothesize that hDlg acts as a MEK2-specific scaffold protein for the ERK signaling pathway, and may improve our understanding of how scaffold proteins, such as hDlg, differentially tune MEK1/MEK2 signaling and cell responses.
机译：人盘大同系物（hDlg），也称为突触相关蛋白97，是一种支架蛋白，是膜相关鸟苷酸激酶家族的成员，与神经元突触和上皮-上皮细胞连接有关，其表达和功能仍然较弱。在大多数组织中，特别是在脉管系统中具有特征。在人类血管组织中，hDlg在平滑肌细胞（VSMC）中高度表达。使用酵母双杂交系统筛选人类主动脉cDNA文库，我们确定了ERK级联成员的促分裂原活化蛋白/细胞外信号响应激酶（ERK）激酶（ERK）激酶（MEK）2作为hDlg结合伴侣。定点诱变显示hDlg的PSD-95，大盘状ZO-1域2和MEK2的C端序列RTAV参与了这一相互作用。人类VSMC和人类胚胎肾293细胞中的免疫共沉淀试验表明，内源性hDlg与MEK2发生物理相互作用，但与MEK1发生物理相互作用。共聚焦显微镜表明，这两种蛋白在融合的人胚胎肾293细胞的质膜内层以及在人VSMC中的核周区域中共定位。另外，hDlg也与这些后面的细胞中的内质网和微管结合。综上所述，这些发现使我们能够假设hDlg作为ERK信号通路的MEK2特异性支架蛋白，并可能增进我们对支架蛋白（例如hDlg）如何差异化调节MEK1 / MEK2信号和细胞反应的理解。

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