TAM receptor tyrosine kinases: Expression, disease and oncogenesis in the central nervous system

Abstract

Receptor tyrosine kinases (RTKs) are cell surface proteins that tightly regulate a variety of downstream intra-cellular processes; ligand-receptor interactions result in cascades of signaling events leading to growth, proliferation, differentiation and migration. There are 58 described RTKs, which are further categorized into 20 different RTK families. When dysregulated or overexpressed, these RTKs are implicated in disordered growth, development, and oncogenesis. The TAM family of RTKs, consisting of Tyro3, Axl, and MerTK, is prominently expressed during the development and function of the central nervous system (CNS). Aberrant expression and dysregulated activation of TAM family members has been demonstrated in a variety of CNS-related disorders and diseases, including the most common but least treatable brain cancer in children and adults: glioblastoma multiforme.

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

“…We then confirmed this finding histologically by Perls' staining to detect ferrous iron deposition at this subacute stage after ICH. AXL and MERTK are expressed on both hematopoietic cells as well as multiple cell types in the CNS (53). We created bone marrow-chimeric mice in which WT (CD45.1) hosts were irradiated and the hematopoietic system reconstituted with either AM DKO Compared with the WT mice, iron-positive cells were increased in the hemorrhagic tissue of AM DKO mice ( Figure 5B).…”

The Role of the TAM Family of Receptor Tyrosine Kinases in Neural Development and Disorders

“…TAM knockout mice provided data on the relationship of TAM receptors and neurodegeneration. Triple TAM knockout mice exhibit cellular degeneration in the neocortex, hippocampus, cerebellum, and rods and cones in the retina [3,12,53].…”

“…RTKs are key regulators of normal cellular processes, and these receptors also play a critical role in the development and progression of many nervous system diseases [2][3][4]. RTKs include 20 families that are distinguished by amino acid sequence identity within the kinase domain and exhibit structural similarities within their extracellular regions [5].…”

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

“…Receptor tyrosine kinases (RTKs) are cell surface proteins responsible for a tight regulation of a broad spectrum of downstream intra-cellular processes [1]. All RTKs are similarly structured, with a ligand binding region in the extracellular domain, a single transmembrane helix and a cytoplasmic region that comprises the protein tyrosine kinase domain as well as additional carboxy-terminal and juxtamembrane regulatory regions [2].…”

“…One or more tyrosines in one receptor within the dimer are transphosphorylated by a neighboring RTK. The phosphorylated receptor subsequently recruits intracellular adaptor and transducing effectors, leading to cascades of signaling events that control growth, proliferation, differentiation and migration [1][2][3].…”