title: 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 nucleusviaa 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.
authors.affiliation: Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yinzhong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiling
authors.initials: X
authors.lastname: Lei
authors.affiliation: Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Niu
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Lanxin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Willemijn M
authors.initials: WM
authors.lastname: Passtoors
authors.affiliation: Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zang
authors.affiliation: Brain Mind Institute-School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Foundation Eclosion, Plan-Les-Ouates, Switzerland.|Campus Biotech Innovation Park, Geneva, Switzerland.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Fraering
authors.affiliation: Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China; fang.wu@sjtu.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
mesh_terms: D021581:Active Transport, Cell Nucleus; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D019913:Nuclear Localization Signals; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D019913:Nuclear Localization Signals; D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; C084944:TYRO3 protein, human; D000076202:c-Mer Tyrosine Kinase; D053829:Amyloid Precursor Protein Secretases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: nuclear translocation; presenilin; protein processing; receptor tyrosine kinase; γ-secretase