Dataset Information

Galectin-3 Stimulates Tyro3 Receptor Tyrosine Kinase and Erk Signalling, Cell Survival and Migration in Human Cancer Cells.

ABSTRACT: The TAM (Tyro3, Axl, MerTK) subfamily of receptor tyrosine kinases (RTKs) and their ligands, Gas6 and protein S (ProS1), are implicated in tumorigenesis and chemoresistance in various cancers. The ?-galactoside binding protein galectin-3 (Gal-3), which is also implicated in oncogenesis, has previously been shown to be a ligand for MerTK. However, the selectivity of Gal-3 for the other TAM receptors, and its TAM-mediated signalling and functional properties in cancer cells, remain to be explored. The present study was aimed at determining these, including through direct comparison of Gal-3 with the two canonical TAM ligands. Exogenous Gal-3 rapidly stimulated Tyro3 receptor phosphorylation to the same extent as the Tyro3 ligand ProS1, but not Axl, in the cultured human cancer cell lines SCC-25 (express both Tyro3 and Axl) and MGH-U3 (express Tyro3 only). Gal-3 also activated intracellular Erk and Akt kinases in both cell lines and furthermore protected cells from acute apoptosis induced by staurosporine but not from serum-starvation induced apoptosis. In addition, Gal-3 significantly stimulated cancer cell migration rate in the presence of the Axl blocker BGB324. Therefore, these results have shown Gal-3 to be a novel agonist for Tyro3 RTK, activating a Tyro3-Erk signalling axis, as well as Akt signalling, in cancer cells that promotes cell survival, cell cycle progression and cell migration. These data therefore reveal a novel mechanism of Tyro3 RTK activation through the action of Gal-3 that contrasts with those of the known TAM ligands Gas6 and ProS1.

SUBMITTER: Al Kafri N

PROVIDER: S-EPMC7407973 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Galectin-3 Stimulates Tyro3 Receptor Tyrosine Kinase and Erk Signalling, Cell Survival and Migration in Human Cancer Cells.

Al Kafri Nour N Hafizi Sassan S

Biomolecules 20200711 7

The TAM (Tyro3, Axl, MerTK) subfamily of receptor tyrosine kinases (RTKs) and their ligands, Gas6 and protein S (ProS1), are implicated in tumorigenesis and chemoresistance in various cancers. The β-galactoside binding protein galectin-3 (Gal-3), which is also implicated in oncogenesis, has previously been shown to be a ligand for MerTK. However, the selectivity of Gal-3 for the other TAM receptors, and its TAM-mediated signalling and functional properties in cancer cells, remain to be explored. ...[more]

PMID: 32664510

Similar Datasets

Project description:Severe appetite and weight loss define the eating disorder anorexia nervosa, and can also accompany the progression of some neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Although acute loss of hypothalamic neurons that produce appetite-stimulating neuropeptide Y (Npy) and agouti-related peptide (Agrp) in adult mice or in mice homozygous for the anorexia (anx) mutation causes aphagia, our understanding of the factors that help maintain appetite regulatory circuitry is limited. Here we identify a mutation (C19T) that converts an arginine to a tryptophan (R7W) in the TYRO3 protein tyrosine kinase 3 (Tyro3) gene, which resides within the anx critical interval, as contributing to the severity of anx phenotypes. Our observation that, like Tyro3-/- mice, anx/anx mice exhibit abnormal secondary platelet aggregation suggested that the C19T Tyro3 variant might have functional consequences. Tyro3 is expressed in the hypothalamus and other brain regions affected by the anx mutation, and its mRNA localization appeared abnormal in anx/anx brains by postnatal day 19 (P19). The presence of wild-type Tyro3 transgenes, but not an R7W-Tyro3 transgene, doubled the weight and lifespans of anx/anx mice and near-normal numbers of hypothalamic Npy-expressing neurons were present in Tyro3-transgenic anx/anx mice at P19. Although no differences in R7W-Tyro3 signal sequence function or protein localization were discernible in vitro, distribution of R7W-Tyro3 protein differed from that of Tyro3 protein in the cerebellum of transgenic wild-type mice. Thus, R7W-Tyro3 protein localization deficits are only detectable in vivo Further analyses revealed that the C19T Tyro3 mutation is present in a few other mouse strains, and hence is not the causative anx mutation, but rather an anx modifier. Our work shows that Tyro3 has prosurvival roles in the appetite regulatory circuitry and could also provide useful insights towards the development of interventions targeting detrimental weight loss.

Project description:Protein phosphorylation serves as a critical biochemical regulator of short-term and long-term synaptic plasticity. Receptor protein tyrosine kinases (RPTKs) including members of the trk, eph and erbB subfamilies have been shown to modulate signaling cascades that influence synaptic function in the central nervous system (CNS). Tyro3 is one of three RPTKs belonging to the "TAM" receptor family, which also includes Axl and Mer. Tyro3 is the most widely expressed of these receptors in the CNS. Despite recent advances suggesting roles for members of this receptor family in the reproductive and immune systems, their functions in the CNS remain largely unexplored. In an effort to elucidate the roles of Tyro3 and its ligand, the protein growth arrest-specific gene6 (Gas6) in the hippocampus and cortex, we performed a detailed study of the localization and signaling of Tyro3 polypeptides in rat hippocampal and cortical neurons. Tyro3 was readily detected in dendrites and in the soma where it was distributed in a punctate pattern. Tyro3 exhibited only a limited level of co-localization with postsynaptic density protein-95 (PSD-95), suggesting that while located within dendrites, it was not confined to the postsynaptic compartment. In addition, Tyro3 was also identified in the axons and growth cones of immature neurons. The prominent expression of Tyro3 in dendrites suggested that it may be capable of modulating signaling pathways triggered by synaptic transmission. We have provided evidence in support of this role by demonstrating that Gas6 induced the phosphorylation of Tyro3 in cortical neurons in vitro, resulting in the recruitment of the mitogen-activated protein kinase (MAPK) and the phosphoinositide-3 kinase (PI(3)K) signaling pathways. As these pathways play critical roles in the induction of hippocampal long-term potentiation (LTP), these findings suggest that Tyro3 signaling may influence synaptic plasticity in the dendritic compartment of hippocampal and cortical neurons.

Dataset Information

Galectin-3 Stimulates Tyro3 Receptor Tyrosine Kinase and Erk Signalling, Cell Survival and Migration in Human Cancer Cells.

Publications

Galectin-3 Stimulates Tyro3 Receptor Tyrosine Kinase and Erk Signalling, Cell Survival and Migration in Human Cancer Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets