Malikova Ilona, Worth Anastassiya, Aliyeva Diana, Khassenova Madina, Kriajevska Marina V, Tulchinsky Eugene
Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, 020000, Kazakhstan.
Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.
Cell Death Dis. 2025 Mar 5;16(1):155. doi: 10.1038/s41419-025-07480-9.
Proteolytic processing of Receptor Tyrosine Kinases (RTKs) leads to the release of ectodomains in the extracellular space. These soluble ectodomains often retain the ligand binding activity and dampen canonical pathways by acting as decoy receptors. On the other hand, shedding the ectodomains may initiate new molecular events and diversification of signalling. Members of the TAM (TYRO3, AXL, MER) family of RTKs undergo proteolytic cleavage, and their soluble forms are present in the extracellular space and biological fluids. TAM receptors are expressed in professional phagocytes, mediating apoptotic cell clearance, and suppressing innate immunity. Enhanced shedding of TAM ectodomains is documented in autoimmune and some inflammatory conditions. Also, soluble TAM receptors are present at high levels in the biological fluids of cancer patients and are associated with poor survival. We outline the biology of TAM receptors and discuss how their proteolytic processing impacts autoimmunity and tumorigenesis. In autoimmune diseases, proteolysis of TAM receptors likely reflects reduced canonical signalling in professional phagocytes. In cancer, TAM receptors are expressed in the immune cells of the tumour microenvironment, where they control pathways facilitating immune evasion. In tumour cells, ectodomain shedding activates non-canonical TAM pathways, leading to epithelial-mesenchymal transition, metastasis, and drug resistance.
受体酪氨酸激酶（RTKs）的蛋白水解加工导致胞外结构域在细胞外空间释放。这些可溶性胞外结构域通常保留配体结合活性，并通过充当诱饵受体来抑制经典信号通路。另一方面，胞外结构域的脱落可能引发新的分子事件和信号多样化。RTKs的TAM（TYRO3、AXL、MER）家族成员会经历蛋白水解切割，其可溶性形式存在于细胞外空间和生物体液中。TAM受体在专职吞噬细胞中表达，介导凋亡细胞清除，并抑制先天性免疫。在自身免疫和一些炎症性疾病中，已证明TAM胞外结构域的脱落增加。此外，可溶性TAM受体在癌症患者的生物体液中含量很高，且与生存率低有关。我们概述了TAM受体的生物学特性，并讨论了它们的蛋白水解加工如何影响自身免疫和肿瘤发生。在自身免疫性疾病中，TAM受体的蛋白水解可能反映了专职吞噬细胞中经典信号传导的减少。在癌症中，TAM受体在肿瘤微环境的免疫细胞中表达，在那里它们控制促进免疫逃逸的信号通路。在肿瘤细胞中，胞外结构域的脱落激活非经典TAM信号通路，导致上皮-间质转化、转移和耐药性。
