title: MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL.
abstract: The receptor tyrosine kinase AXL regulates melanoma cell proliferation and migration. We now demonstrate that AXL and the related kinase MERTK are alternately expressed in melanoma and are associated with different transcriptional signatures. MERTK-positive melanoma cells are more proliferative and less migratory than AXL-positive melanoma cells and overexpression of AXL increases cell motility relative to MERTK. MERTK is expressed in up to 50% of melanoma cells and shRNA-mediated knockdown of MERTK reduces colony formation and cell migration in a CDC42-dependent fashion. Targeting MERTK also decreases cell survival and proliferation in an AKT-dependent manner. Finally, we identify a novel mutation in the kinase domain of MERTK, MERTK(P) (802S) , that increases the motility of melanoma cells relative to wild-type MERTK. Together, these data demonstrate that MERTK is a possible therapeutic target in melanoma, that AXL and MERTK are associated with differential cell behaviors, and that mutations in MERTK may contribute to melanoma pathogenesis.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Tworkoski
authors.forename: James T
authors.initials: JT
authors.lastname: Platt
authors.forename: Antonella
authors.initials: A
authors.lastname: Bacchiocchi
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003592:Cytophotometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D020764:cdc42 GTP-Binding Protein; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human