酪氨酸激酶RTK（58种，20类受体型）是位于细胞膜上的信号转导开关，通过调控其活力已成功发展了多种靶向药物，如抗癌明星药物易瑞沙Iressa®、特罗凯Tarceva®、索坦Sunitinib®、 赫赛汀Herceptin®和阿雷替尼Alecensa®等。

AXL(Anexelekto；Greek for “uncontrolled”)是一种进化晚期才出现的受体型酪氨酸激酶。最近发现其过度表达可介导肿瘤化疗产生的多种耐药性，但具体的分子机制还不明确。AXL的靶向抑制剂R428已于2011年进入临床I期。

上海交大系统生物医学研究院吴方课题组自2012年起研究AXL翻译后加工和稳定性的分子机制，利用小分子探针工具结合生物化学方法，发现AXL膜蛋白的稳态受alpha分泌酶、gamma分泌酶和蛋白酶体联合控制。AXL可被分泌酶剪切产生胞内片断ICD，该胞内片断可通过一个新发现的HRRKK的核定位信号入核进一步调控基因活力。

临床在研药物R428可抑制AXL的磷酸化，打破膜上AXL含量的稳态调控，加速AXL经分泌酶剪切的代谢通路，从而下调AXL膜上的表达量。而抑制AXL的膜内剪切可显著增高非小细胞肺癌细胞对Tarceva®药物的耐药性。这些结果提示，AXL介导的肿瘤耐药性可能与分泌酶调控其稳态密切相关。

这一新发现的AXL翻译后加工机制，可为治疗肿瘤耐药性提供新靶点和思路。

该工作主要完成人为博士研究生卢银忠，研究结果于2016年12月发表在美国实验生物学联合会会刊The FASEB (Federation of American Societies for Experimental Biology) Journal上。吴方课题组目前正在针对这一新机制，研究特异加速AXL降解的创新药物先导物，希望可为耐药性肿瘤的治疗提供新方法和新药物。该研究工作得到国家自然科学基金的支持。（来源：生物通）

Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells

Abstract  Deregulation of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases (RTKs) has recently been demonstrated to predominately promote survival and chemoresistance of cancer cells. Intramembrane proteolysis mediated by presenilin/γ-secretase is known to regulate the homeostasis of some RTKs. In the present study, we demonstrate that AXL, but not TYRO3 or MERTK, is efficiently and sequentially cleaved by α- and γ-secretases in various types of cancer cell lines. Proteolytic processing of AXL redirected signaling toward a secretase-mediated pathway, away from the classic, well-known, ligand-dependent canonical RTK signaling pathway. The AXL intracellular domain cleavage product, but not full-length AXL, was further shown to translocate into the nucleus via a nuclear localization sequence that harbored a basic HRRKK motif. Of interest, we found that the γ-secretase-uncleavable AXL mutant caused an elevated chemoresistance in non-small-cell lung cancer cells. Altogether, our findings suggest that AXL can undergo sequential processing mediated by various proteases kept in a homeostatic balance. This newly discovered post-translational processing of AXL may provide an explanation for the diverse functions of AXL, especially in the context of drug resistance in cancer cells.-Lu, Y., Wan, J., Yang, Z., Lei, X., Niu, Q., Jiang, L., Passtoors, W. M., Zang, A., Fraering, P. C., Wu, F. Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells.

原文链接：http://www.fasebj.org/content/early/2016/12/29/fj.201600702R.full.pdf