Molecular pathways: MERTK signaling in cancer

Abstract

MERTK is a receptor tyrosine kinase of the TAM (Tyro3, Axl, MERTK) family, with a defined spectrum of normal expression. However, MERTK is overexpressed or ectopically expressed in a wide variety of cancers, including leukemia, non-small cell lung cancer, glioblastoma, melanoma, prostate cancer, breast cancer, colon cancer, gastric cancer, pituitary adenomas, and rhabdomyosarcomas, potentially resulting in the activation of several canonical oncogenic signaling pathways. These include the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, as well as regulation of signal transducer and activator of transcription family members, migration-associated proteins including the focal adhesion kinase and myosin light chain 2, and prosurvival proteins such as survivin and Bcl-2. Each has been implicated in MERTK physiologic and oncogenic functions. In neoplastic cells, these signaling events result in functional phenotypes such as decreased apoptosis, increased migration, chemoresistance, increased colony formation, and increased tumor formation in murine models. Conversely, MERTK inhibition by genetic or pharmacologic means can reverse these pro-oncogenic phenotypes. Multiple therapeutic approaches to MERTK inhibition are currently in development, including ligand "traps", a monoclonal antibody, and small-molecule tyrosine kinase inhibitors.

Figure 1:

The MERTK Signaling Network. Multiple pro-oncogenic signaling pathways have been implicated downstream of MERTK activation. These include pathways promoting survival, increasing migration, and inhibiting apoptosis. The ligands Gas6, protein S, Tubby, Tulp1, and Galectin-3 all induce MERTK auto-phosphorylation, to initiate the signaling cascades depicted below. More recently, MERTK has been shown to be regulated by two miRNAs – miR126 and miR335, and may also have direct effects on gene transcription. Inhibitors of MERTK, including ligand traps, a monoclonal antibody, and small molecule inhibitors, are currently in pre-clinical development.