The Tyro3, Axl, and MerTK (TAM) receptors are three homologous Type I Receptor Tyrosine Kinases that have important homeostatic functions in multicellular organisms by regulating the clearance of apoptotic cells (efferocytosis). Pathologically, TAM receptors are overexpressed in a wide array of human cancers, and often associated with aggressive tumor grade and poor overall survival. In addition to their expression on tumor cells, TAMs are also expressed on infiltrating myeloid-derived cells in the tumor microenvironment, where they appear to act akin to negative immune checkpoints that impair host anti-tumor immunity. The ligands for TAMs are two endogenous proteins, Growth Arrest-Specific 6 (Gas6) and Protein S (Pros1), that function as bridging molecules between externalized phosphatidylserine (PtdSer) on apoptotic cells and the TAM ectodomains. One interesting feature of TAMs biology is that their ligand proteins require specific post-translational modifications to acquire activities. This chapter summarized these important modifications and explained the molecular mechanisms behind such phenomenon. Current evidences suggest that these modifications help Gas6/Pros1 to achieve optimal PtdSer-binding capacities. In addition, this chapter included recent discovery of regulating machineries of PtdSer dynamic across the plasma membrane, as well as their potential impacts in the tumor microenvironment. Taken together, this review highlights the importance of the upstream PtdSer and Gas6 in regulating TAMs' function and hope to provide researchers with new perspectives to inspire future studies of TAM receptors in human disease models.

Tyro3、Axl 和 MerTK (TAM) 受体是三种同源的 I 型受体酪氨酸激酶，它们通过调节凋亡细胞的清除（胞吞作用）在多细胞生物中具有重要的稳态功能。在病理学上，TAM 受体在多种人类癌症中过度表达，并且通常与侵袭性肿瘤分级和较差的总体存活率相关。除了在肿瘤细胞上表达外，TAM 还在肿瘤微环境中浸润的髓样细胞上表达，在那里它们的作用类似于削弱宿主抗肿瘤免疫的阴性免疫检查点。TAM 的配体是两种内源性蛋白质，Growth Arrest-Specific 6 (Gas6) 和 Protein S (Pros1)，它们充当凋亡细胞上外化磷脂酰丝氨酸 (PtdSer) 和 TAM 胞外域之间的桥接分子。TAM 生物学的一个有趣特征是它们的配体蛋白需要特定的翻译后修饰才能获得活性。本章总结了这些重要的修饰，并解释了这种现象背后的分子机制。目前的证据表明，这些修改有助于 Gas6/Pros1 实现最佳的 PtdSer 结合能力。此外，本章还包括最近发现的跨质膜 PtdSer 动态调节机制，以及它们对肿瘤微环境的潜在影响。总之，这篇综述强调了上游 PtdSer 和 Gas6 在调节 TAM 功能中的重要性，并希望为研究人员提供新的视角，以激发未来人类疾病模型中 TAM 受体的研究。