Search

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/gamma-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 alpha-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 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 g-secretase-uncleavable AXL mutant caused an elevated chemoresistance in non-small-cell lung cancer cells. Altogether, our findings suggest thatAXL can undergo sequential processing mediated by various proteases kept in a homeostatic balance. This newly discovered post-translational processing ofAXL 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

Dehydroxymethylepoxyquinomicin (DHMEQ) is a low-m.w. compound that strongly inhibits NF-κB. DHMEQ directly binds to NF-κB subunits and thereby inhibits their nuclear translocation and DNA binding. ...

Transcription of NFkB-dependent genes is regulated by the nuclear translocation and accumulation of IkBa. In the nucleus, IkBa suppresses transcription of NFkB-dependent pro-inflammatory and anti-a...

Heat shock protein 90 (hsp90) regulates the stability and function of several kinases, including IKB kinases (IKKs). We investigated the mechanisms by which hsp90 inhibitors prevent induction of NF...

Calcineurin regulates the dephosphorylation and nuclear translocation of the cardiac hypertophy transcription factor, Nuclear Factor of Activated T-cells (NFAT). O-linked beta-N-acetyl glucosamine ...