ALK binds ALKAL ligand

Signaling through the ALK receptor is activated by the binding of ALKAL ligand to the receptor extracellular region (Zhang et al, 2014; Guan et al, 2015; Reshetnyak et al, 2015; Reshetnyak et al, 2018; Reshetnyak et al, 2021; De Munck et al, 2021). <br>There are two human ALKAL proteins, ALKAL1 (also known as FAM150A) and ALKAL2 (also known as FAM150B). ALKAL1 and 2 were initially characterized as ligands for the ALK-related receptor leukocyte tyrosine kinase (LTK), and subsequently shown to bind to ALK as well (Zhang et al, 2014; Guan et al, 2015). Further studies revealed differences in ligand affinity for the two receptors, however, likely mediated by the differences in the extracellular domains of the two receptors. Although LTK is potently activated by both ALKAL1 and 2, robust activation of ALK in physiological contexts is only seen with ALKAL2 (Guan et al, 2015; Reshetnyak et al, 2015). <br>There is conflicting evidence as to whether ALKAL2 binds ALK as a monomer ((De Munck et al, 2021) or a dimer (Reshetnyak et al, 2018; Reshetnyak et al 2021). In this pathway, ALKAL2 is depicted as binding ALK as a dimer linked by interchain disulphide bond at residue C66 (Reshetnyak et al, 2018; Reshetnyak et al, 2021). Binding of ALKAL2 to the ALK receptor is also facilitated by binding of heparin to ALK (De Munck et al, 2021).

通过 ALK 受体的信号传导被 ALKAL 配体与受体胞外区域的结合所激活（张等，2014；关等，2015；雷斯尼雅克等，2015；雷斯尼雅克等，2018；雷斯尼雅克等，2021；德·蒙克等，2021）。人类存在两种 ALKAL 蛋白，即 ALKAL1（亦称 FAM150A）和 ALKAL2（亦称 FAM150B）。ALKAL1 和 2 起初被鉴定为 ALK 相关受体白细胞酪氨酸激酶（LTK）的配体，随后亦被发现与 ALK 结合（张等，2014；关等，2015）。进一步的研究揭示了两种受体的配体亲和力存在差异，这些差异可能是由两种受体的胞外结构域的差异所介导。尽管 LTK 可被 ALKAL1 和 2 强力激活，但在生理环境中，仅观察到 ALKAL2 对 ALK 的稳健激活（关等，2015；雷斯尼雅克等，2015）。关于 ALKAL2 是否以单体（德·蒙克等，2021）或二聚体（雷斯尼雅克等，2018；雷斯尼雅克等，2021）形式与 ALK 结合，存在相互矛盾的证据。在此通路中，ALKAL2 被描绘为通过在 C66 位点的链间二硫键连接的二聚体形式与 ALK 结合（雷斯尼雅克等，2018；雷斯尼雅克等，2021）。ALKAL2 与 ALK 受体的结合亦受到肝素与 ALK 结合的促进（德·蒙克等，2021）。