The role of glycosylation in receptor activation

糖基化在受体激活中的作用

• 批准号: 203498-2008
• 负责人: Szewczuk, Myron
• 金额: $ 2.92万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=514117
• 关键词: role; glycosylation; receptor; activation

Mammalian receptor tyrosine kinases (RTKs) are the high affinity cell surface receptors for many growth factors, cytokines and hormones. Approximately 20 different RTK classes have been identified. Most RTKs are single, glycosylated subunit receptors but some for example, the insulin receptor exist as multimeric complexes. When a growth factor binds to the extracellular domain of an RTK, its dimerization is triggered with other adjacent RTKs. Dimerization leads to a rapid activation of the receptor's cytoplasmic kinase domains. The activated receptor then becomes autophosphorylated on multiple specific intracellular tyrosine residues. Although the signaling pathways of RTKs are well characterized, the parameters controlling dimerization and the interactions between the receptors and their ligands still remain poorly defined. For nerve growth factor (NGF) TrkA receptors, glycosylation is required to localize the receptor to the cell surface where glycosylation was suggested to prevent receptor autophosphorylation Indeed, glycosylation of cell membrane bound RTKs may be an important requirement for their transport and function. For an example, partial glycosylation is an important requirement for at least the processing and/or hormone-binding activity of RTK insulin receptor, and epidermal-growth-factor receptor. To date, the precise role of RTK glycosylation in receptor activation is unknown. Here, we discover a direct link between Trk glycosylation and receptor activation following natural ligand interaction (Woronowicz et al., Glycobiology 17:10-24, 2007). Our recent preliminary data indicate that ligand binding to Trk as well as epidermal growth factor receptors (EGFR) and insulin receptors induces lysosomal Neu1 sialidase activity which influences the receptor desialylation and, consequently, the induction of RTK activation. These observations suggest for the first time that RTK activation is regulated by lysosomal Neu1 sialidase induction, and thus we identify a critical parameter involved with ligand binding to RTKs, which has not been previously observed. Neu1 sialidase may be a common master enzyme regulating the process of dimerization and activation of RTK receptors.

哺乳动物受体酪氨酸激酶（RTKs）是许多生长因子、细胞因子和激素的高亲和力细胞表面受体。已经确定了大约20种不同的RTK类。大多数RTK是单一的糖基化亚基受体，但有些例如胰岛素受体作为多聚体复合物存在。当生长因子与RTK的细胞外结构域结合时，其二聚化被其他相邻的RTK触发。二聚化导致受体胞质激酶结构域的快速活化。然后，激活的受体在多个特定的细胞内酪氨酸残基上自磷酸化。尽管RTK的信号传导途径已被很好地表征，但控制二聚化的参数以及受体与其配体之间的相互作用仍然定义不清。对于神经生长因子（NGF）TrkA受体，需要糖基化以将受体定位于细胞表面，其中糖基化被建议以防止受体自磷酸化。实际上，细胞膜结合的RTK的糖基化可能是其运输和功能的重要要求。例如，部分糖基化是至少RTK胰岛素受体和表皮生长因子受体的加工和/或酶结合活性的重要要求。迄今为止，RTK糖基化在受体活化中的确切作用尚不清楚。在此，我们发现Trk糖基化和天然配体相互作用后的受体活化之间的直接联系（Woronowicz等人，Glycobiology 17：10-24，2007）。我们最近的初步数据表明，配体与Trk以及表皮生长因子受体（EGFR）和胰岛素受体的结合诱导溶酶体Neu 1唾液酸酶活性，其影响受体去唾液酸化，从而诱导RTK活化。这些观察结果首次表明，RTK激活调节溶酶体Neu 1唾液酸酶诱导，因此，我们确定了一个关键参数与配体结合RTK，这是以前没有观察到的。Neu 1唾液酸酶可能是调节RTK受体二聚化和活化过程的常见主酶。