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.

Mer receptor tyrosine kinase is a therapeutic target in pre–B-cell acute lymphoblastic leukemia

“…Although the role of Mer as an extracellular receptor and promoter of intracellular signal transduction has been previously reported, Mer has also been found to internalize and localize to the nucleus, 35 suggesting that it may have a role in regulation of gene expression. Comparison of transcriptional differences between our control and Mer knockdown B-ALL cells after treatment with Gas6 or methotrexate demonstrated decreased prosurvival BCL-XL, PI3K, and PKC expression and increased proapoptotic BAX, NOXA, and PUMA expression in the knockdown cells, further demonstrating a survival advantage of lymphoblast signaling through Mer.…”

Molecular Pathways: MERTK Signaling in Cancer

“…Related to the concept of receptor trafficking, a recent study found MERTK to be located not only at the cell surface, but also in the nucleus. Consensus nuclear localization sequences have also been identified in the MERTK gene (52). This raises the possibility that MERTK may have effects on gene transcription.…”

MERTK receptor tyrosine kinase is a therapeutic target in melanoma

“…The multiple MERTK species observed are likely due to posttranslational modifications, most notably, glycosylation. MERTK has been described to be both heavily and differentially glycosylated through Asn-linked glycosylation (23,24). Treatment of melanoma cell lysates with PNGase F resulted in 1 predominant lower molecular weight band (Supplemental Figure 2).…”