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 recentlybeendemonstratedtopredominatelypromote survival andchemoresistance of cancer cells. Intramembrane proteolysis mediated by presenilin/g-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 a- and g-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.TheAXL intracellulardomain cleavage product, but not full-length AXL,was further shown to translocate into the nucleus via a nuclear localization sequence that harbored a basicHRRKKmotif.Of interest, we found that the g-secretase-uncleavable AXL mutant caused an elevated chemoresistance in non-small-cell lung cancer cells. Altogether, our findings suggest thatAXL can undergo sequential processingmediated by various proteases kept in a homeostatic balance. This newly discovered post-translational processing of AXL may provide an explanation for thediverse functions ofAXL,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.