MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL

Pigment Cell Melanoma Res. 2013 Jul;26(4):527-41. doi: 10.1111/pcmr.12110. Epub 2013 May 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Cytophotometry
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Melanoma / metabolism*
  • Neoplasm Metastasis
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins / physiology*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Signal Transduction
  • Skin Neoplasms / metabolism
  • c-Mer Tyrosine Kinase
  • cdc42 GTP-Binding Protein / metabolism

Substances

  • Proto-Oncogene Proteins
  • MERTK protein, human
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase
  • c-Mer Tyrosine Kinase
  • cdc42 GTP-Binding Protein