Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that harbours a tyrosine kinase domain in its intracellular region and is expressed in both central and peripheral nervous systems. RTKs are activated upon ligand binding and receptor clustering; however, ALK remains an orphan receptor despite its pathological significance, especially in malignancy. Recent biochemical work showed that heparan sulphate (HS), an unbranched sulphated glycan, acts as a ligand for and activates ALK. Here, we show that dermatan sulphate (DS, chondroitin sulphate B) directly interacts with the extracellular N-terminal region of ALK as well as HS. The tetrasaccharide of DS was required and was sufficient for inducing autophosphorylation of ALK at tyrosine 1604, a marker for activated ALK. Interestingly, longer oligosaccharides caused enhanced activation of ALK, as was the case for HS. Our results provide a novel example of glycans as signalling molecules and shed light on the pathophysiological roles of ALK.

中文翻译：

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硫酸皮肤素是间变性淋巴瘤激酶的活化配体

间变性淋巴瘤激酶 (ALK) 是一种受体酪氨酸激酶 (RTK)，在其细胞内区域含有酪氨酸激酶结构域，并在中枢和外周神经系统中表达。RTK 在配体结合和受体聚集时被激活；然而，尽管 ALK 具有病理学意义，但它仍然是一种孤儿受体，尤其是在恶性肿瘤中。最近的生化工作表明，硫酸乙酰肝素 (HS) 是一种无支链的硫酸化聚糖，可作为 ALK 的配体并激活。在这里，我们表明硫酸皮肤素（DS，硫酸软骨素 B）直接与 ALK 的细胞外 N 末端区域以及 HS 相互作用。DS 的四糖是必需的，并且足以诱导 ALK 在酪氨酸 1604 处的自磷酸化，这是活化 ALK 的标志物。有趣的是，较长的寡糖导致 ALK 的活化增强，HS 就是这种情况。我们的研究结果提供了聚糖作为信号分子的一个新例子，并阐明了 ALK 的病理生理学作用。