The role of glycosylation in receptor activation

哺乳动物受体酪氨酸激酶(RTK)是多种生长因子、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个不同的RTK类别。大多数RTK是单一的糖基化的亚单位受体，但也有一些，例如，胰岛素受体以多聚体复合体的形式存在。当一种生长因子与RTK的胞外结构域结合时，它的二聚化就会被其他相邻的RTK触发。二聚化导致受体胞质激活区的快速激活。然后激活的受体在多个特定的细胞内酪氨酸残基上自动磷酸化。虽然RTK的信号通路已经被很好地描述，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不清楚。对于神经生长因子(NGF)TrkA受体，需要糖基化来将受体定位到细胞表面，而糖基化是防止受体自磷酸化的关键。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加工和/或激素结合活性的重要要求。到目前为止，RTK糖基化在受体激活中的确切作用尚不清楚。在这里，我们发现了Trk糖基化和天然配体相互作用后的受体激活之间的直接联系(Woronowicz等人，GlycoBiology 17：10-24,2007)。我们最近的初步数据表明，与Trk以及表皮生长因子受体(EGFR)和胰岛素受体结合的配体可以诱导溶酶体Neu1唾液酸酶活性，从而影响受体的失活，从而诱导RTK的激活。这些观察首次表明RTK的激活是由溶酶体Neu1唾液酸酶诱导调节的，因此我们确定了一个与RTK的配体结合有关的关键参数，这是以前没有观察到的。NEU1唾液酸酶可能是调节RTK受体二聚化和激活过程的共同主酶。

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.