title: Prolonged exposure to a Mer ligand in leukemia: Gas6 favors expression of a partial Mer glycoform and reveals a novel role for Mer in the nucleus.
abstract: Mer tyrosine kinase is ectopically expressed in acute lymphoblastic leukemia and associated with enhanced chemoresistance and disease progression. While such effects are generally ascribed to increased engagement of oncogenic pathways downstream of Mer stimulation by its ligand, Gas6, Mer has not been characterized beyond the scope of its signaling activity. The present study explores Mer behavior following prolonged exposure to Gas6, a context similar to the Gas6-enriched microenvironment of the bone marrow, where a steady supply of ligand facilitates continuous engagement of Mer and likely sustains the presence of leukemic cells. Long-term Gas6 exposure induced production of a partially N-glycosylated form of Mer from newly synthesized stores of protein. Preferential expression of the partial Mer glycoform was associated with diminished levels of Mer on the cell surface and altered Mer localization within the nuclear-soluble and chromatin-bound fractions. The presence of Mer in the nucleus is a novel finding for this receptor, and the glycoform-specific preferences observed in each nuclear compartment suggest that glycosylation may influence Mer function within particular subcellular locales. Previous studies have established Mer as an attractive cancer biologic target, and understanding the complexity of its activity has important implications for potential strategies of Mer inhibition in leukemia therapy. Our results identify several novel features of Mer that expand the breadth of its functions and impact the development of therapeutic modalities designed to target Mer.
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Justine
authors.initials: J
authors.lastname: Migdall-Wilson
authors.forename: Christine
authors.initials: C
authors.lastname: Bates
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schlegel
authors.forename: Luis
authors.initials: L
authors.lastname: Brandão
authors.forename: Rachel M A
authors.initials: RM
authors.lastname: Linger
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham
mesh_terms: D000595:Amino Acid Sequence; D002451:Cell Compartmentation / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D002467:Cell Nucleus / Q000187:drug effects* / Q000201:enzymology*; D017124:Conserved Sequence; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology*; D007938:Leukemia / Q000201:enzymology*; D008024:Ligands; D008969:Molecular Sequence Data; D008970:Molecular Weight; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals / Q000737:chemistry; D014176:Protein Biosynthesis / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C097072:MERTK protein, human