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

• Published in: The FASEB journal 2017-04, Vol.31 (4), p.1382-1397
• Main Authors: Lu, Yinzhong, Wan, Jun, Yang, Zhifeng, Lei, Xiling, Niu, Qi, Jiang, Lanxin, Passtoors, Willemijn M., Zang, Aiping, Fraering, Patrick C., Wu, Fang
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Amyloid Precursor Protein Secretases - metabolism; Axl protein; c-Mer Tyrosine Kinase; Cancer; Cell Nucleus - metabolism; Chemoresistance; Deregulation; Drug resistance; Drug Resistance, Neoplasm - genetics; HCT116 Cells; HEK293 Cells; HeLa Cells; Homeostasis; Humans; Information processing; Intracellular; Intracellular signalling; Kinases; Localization; Lung cancer; Mutation; Nuclear Localization Signals; nuclear translocation; Nuclei; Nuclei (cytology); Post-translation; Presenilin; protein processing; Protein-tyrosine kinase receptors; Proteolysis; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - chemistry; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; receptor tyrosine kinase; Secretase; Signal transduction; Tumor cell lines; Tyrosine; γ‐secretase
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201600702R

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. FASEB J. 31, 1382–1397 (2017) www.fasebj.org