文章：

TAM家族：在癌症中出错的磷脂酰丝氨酸感知受体酪氨酸激酶

The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer

原文发布日期：2014-11-24

DOI: 10.1038/nrc3847

类型: Review Article

开放获取: 否

要点：

1. TYRO3, AXL and MERTK (TAM) rely on a unique mode of receptor tyrosine kinase (RTK) regulation — which involves a protein ligand and a lipid (phosphatidylserine) complex that binds to the extracellular domain — to trigger dimerization and kinase activation.
2. MERTK initiates efferocytosis in macrophages and epithelial cells, which has a crucial role in the efficient clearance of apoptotic material.
3. MERTK and AXL function in innate immune cells to suppress inflammatory responses.
4. Genetic deletion of Mertk in mice leads to autoimmunity, and additional deletion of Axl and Tyro3 increases the autoimmune, inflammatory response.
5. TAM RTKs carry out their physiological innate immune functions within tumours and thereby promote an immunosuppressive tumour microenvironment.
6. TAM RTKs and their ligands are overexpressed in neoplastic cells. Autocrine and paracrine stimulation of aberrantly expressed TAM RTKs provide intrinsic survival signals and promote resistance to molecularly targeted and cytotoxic therapies.
7. AXL has normal roles in vasculogenesis and in the migration of cells during development; AXL expression correlates with metastasis, epithelial-to-mesenchymal transition and motility in tumours.
8. TAM RTKs represent a dual target in neoplastic disease given their intrinsic roles in tumour cell survival and chemoresistance, and their immunosuppressive roles in the tumour microenvironment.

要点翻译：

1. TYRO3、AXL和MERTK（TAM受体酪氨酸激酶）依赖独特的调控机制——通过蛋白配体与磷脂（磷脂酰丝氨酸）结合形成复合物，与胞外结构域结合诱发二聚化及激酶活化。  
2. MERTK在巨噬细胞和上皮细胞中启动胞葬作用，对凋亡物质的高效清除至关重要。  
3. MERTK与AXL在天然免疫细胞中发挥抑制炎症反应的功能。  
4. 小鼠Mertk基因缺失会引发自身免疫反应，若同时缺失Axl与Tyro3则会加剧自身免疫性炎症反应。  
5. TAM受体酪氨酸激酶在肿瘤内执行其生理性天然免疫功能，从而促进免疫抑制性肿瘤微环境的形成。  
6. TAM受体及其配体在肿瘤细胞中过度表达。异常表达的TAM受体通过自分泌与旁分泌途径接收刺激，传递细胞内在存活信号，并促进对分子靶向治疗与细胞毒性治疗的耐药性。  
7. AXL在血管生成和发育过程中的细胞迁移中具有正常生理功能；其表达水平与肿瘤转移、上皮-间质转化及运动能力相关。  
8. TAM受体酪氨酸激酶在肿瘤疾病中构成双重靶点：既通过调控肿瘤细胞存活与化疗耐药发挥内在作用，又在肿瘤微环境中履行免疫抑制功能。

英文摘要：

The TYRO3, AXL (also known as UFO) and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are aberrantly expressed in multiple haematological and epithelial malignancies. Rather than functioning as oncogenic drivers, their induction in tumour cells predominately promotes survival, chemoresistance and motility. The unique mode of maximal activation of this RTK family requires an extracellular lipid–protein complex. For example, the protein ligand, growth arrest-specific protein 6 (GAS6), binds to phosphatidylserine (PtdSer) that is externalized on apoptotic cell membranes, which activates MERTK on macrophages. This triggers engulfment of apoptotic material and subsequent anti-inflammatory macrophage polarization. In tumours, autocrine and paracrine ligands and apoptotic cells are abundant, which provide a survival signal to the tumour cell and favour an anti-inflammatory, immunosuppressive microenvironment. Thus, TAM kinase inhibition could stimulate antitumour immunity, reduce tumour cell survival, enhance chemosensitivity and diminish metastatic potential.

摘要翻译： 

TYRO3、AXL（又称UFO）和MERTK（TAM）家族受体酪氨酸激酶（RTKs）在多种血液和上皮恶性肿瘤中异常表达。它们并非作为致癌驱动因子，而是在肿瘤细胞中主要促进存活、化疗耐药性和运动能力。这一RTK家族的最大激活模式需要一种胞外脂质-蛋白复合物。例如，蛋白配体生长停滞特异性蛋白6（GAS6）结合到凋亡细胞膜外翻的磷脂酰丝氨酸（PtdSer）上，从而激活巨噬细胞上的MERTK。这触发凋亡物质的吞噬及随后的抗炎性巨噬细胞极化。在肿瘤中，自分泌和旁分泌配体及凋亡细胞丰富，为肿瘤细胞提供存活信号，并有利于形成抗炎、免疫抑制的微环境。因此，抑制TAM激酶可刺激抗肿瘤免疫，减少肿瘤细胞存活，增强化疗敏感性并降低转移潜能。

原文链接：

The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer