title: AXL receptor signalling suppresses p53 in melanoma through stabilization of the MDMX-MDM2 complex.
abstract: Deregulation of the tyrosine kinase signalling is often associated with tumour progression and drug resistance, but its underlying mechanisms are only partly understood. In this study, we investigated the effects of the receptor tyrosine kinase AXL on the stability of the MDMX-MDM2 heterocomplex and the activity of p53 in melanoma cells. Our data demonstrated that AXL overexpression or activation through growth arrest-specific 6 (Gas6) ligand stimulation increases MDMX and MDM2 protein levels and decreases p53 activity. Upon activation, AXL stabilizes MDMX through a post-translational modification that involves phosphorylation of MDMX on the phosphosite Ser314, leading to increased affinity between MDMX and MDM2 and favouring MDMX nuclear translocation. Ser314 phosphorylation can also protect MDMX from MDM2-mediated degradation, leading to stabilization of the MDMX-MDM2 complex. We identified CDK4/6 and p38 MAPK as the two kinases mediating AXL-induced modulation of the MDMX-MDM2 complex, and demonstrated that suppression of AXL, either through siRNA silencing or pharmacological inhibition, increases expression levels of p53 target genes P21, MDM2, and PUMA, improves p53 pathway response to chemotherapy, and sensitizes cells to both Cisplatin and Vemurafenib. Our findings offer an insight into a novel signalling axis linking AXL to p53 and provide a potentially druggable pathway to restore p53 function in melanoma.
authors.affiliation: John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: de Polo
authors.affiliation: John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.|Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Zhongling
authors.initials: Z
authors.lastname: Luo
authors.affiliation: John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Casimiro
authors.initials: C
authors.lastname: Gerarduzzi
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Little
authors.affiliation: John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Yuan
mesh_terms: D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000077484:Vemurafenib; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D018797:Cell Cycle Proteins; D007211:Indoles; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D010768:Phosphoserine; D000077484:Vemurafenib; D051736:Proto-Oncogene Proteins c-mdm2; D020794:Receptor Protein-Tyrosine Kinases; D018844:Cyclin-Dependent Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: AXL; CDK4/6; MDM2; MDMX; melanoma; p53