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首页> 外文期刊>Molecular and Cellular Biology >Mutations in the WSAWSE and cytosolic domains of the erythropoietin receptor affect signal transduction and ligand binding and internalization.
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Mutations in the WSAWSE and cytosolic domains of the erythropoietin receptor affect signal transduction and ligand binding and internalization.

机译：WSAWSE和促红细胞生成素受体胞质结构域中的突变影响信号转导，配体结合和内在化。

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摘要

The terminal development of erythroid progenitor cells is promoted in part through the interaction of erythropoietin (EPO) with its cell surface receptor. This receptor and a growing family of related cytokine receptors share homologous extracellular features, including a well-conserved WSXWS motif. To explore the functional significance of this motif in the murine EPO receptor, five WSAWSE mutants were prepared and their signal-transducing, ligand binding, and endocytotic properties were compared. EPO receptors mutated at tryptophan residues (W-232, W-235----G; W-235----G; W-235----F) failed to mediate EPO-induced growth or pp100 phosphorylation, while S-236----T and E-237----K mutants exhibited partial to full activity (50 to 100% of wild-type growth and induced phosphorylation). Ligand affinity was reduced for mutant receptors (two- to fivefold), yet expression at the cell surface for all receptors was nearly equivalent. Also, the ability of mutated receptors to internalize ligand was either markedly reduced or abolished (W-235----F), indicating a role for the WSAWSE region in hormone internalization. Interestingly, receptor forms lacking 97% of the cytosolic domain (no signal-transducing capacity; binding affinity reduced two- to threefold) internalized EPO efficiently. This and all WSAWSE receptor forms studied also mediated specific cross-linking of 125I-EPO to three accessory membrane proteins (M(r)s, 120,000, 105,000, and 93,000). These findings suggest that the WSAWSE domain of the EPO receptor is important for EPO-induced signal transduction and ligand internalization. In contrast, although the cytosolic domain is required for growth signaling, it appears nonessential for efficient endocytosis.
机译：红细胞祖细胞的末端发育部分通过促红细胞生成素（EPO）与其细胞表面受体的相互作用来促进。该受体和一个不断增长的相关细胞因子受体家族共享同源的细胞外特征，包括一个保守的WSXWS基序。为了探索该基序在鼠EPO受体中的功能意义，制备了五个WSAWSE突变体，并比较了它们的信号传导，配体结合和内吞特性。 EPO受体在色氨酸残基处突变（W-232，W-235 ---- G; W-235 ---- G; W-235 ---- F）无法介导EPO诱导的生长或pp100磷酸化，而S-236 ---- T和E-237 ---- K突变体表现出部分至全部活性（野生型生长和诱导的磷酸化的50％至100％）。配体受体的配体亲和力降低（两倍至五倍），但所有受体在细胞表面的表达几乎相等。而且，突变的受体内化配体的能力显着降低或消失（W-235 ---- F），表明WSAWSE区在激素内化中发挥了作用。有趣的是，受体形式缺乏97％的胞质结构域（无信号传导能力;结合亲和力降低了2至3倍）有效地内化了EPO。研究的这种和所有WSAWSE受体形式还介导了125I-EPO与三种辅助膜蛋白（M（r），120,000、105,000和93,000）的特异性交联。这些发现表明，EPO受体的WSAWSE结构域对于EPO诱导的信号转导和配体内在化是重要​​的。相反，尽管胞质结构域是生长信号转导所必需的，但对于有效的内吞作用似乎并不重要。

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