Identification of signalling pathways activated by Tyro3 that promote cell survival, proliferation and invasiveness in human cancer cells

Abstract

Tyro3 is a member of the TAM subfamily of receptor tyrosine kinases alongside Axl and MerTK, which are activated by homologous ligands Gas6 and protein S. The TAMs activate signalling pathways that mediate diverse functions including cell survival, proliferation, phagocytosis and immune regulation, and defects in TAM-dependent processes are associated with the development of human autoimmune diseases and numerous cancers. In this study, we have focused on the signalling and functional roles of Tyro3, about which much remains unknown. For this purpose, we used cultured human cancer cell lines with different levels of TAM expression to reveal the relative significance of Tyro3 amongst the TAMs. Knockdown of Tyro3 expression by siRNA in MGH-U3 cells, which express Tyro3 as sole TAM, caused a reduction in cell viability, which could not be rescued by TAM ligand, demonstrating the dependence of these cells solely on Tyro3. In contrast, the reduced viability of SCC-25 cells upon Tyro3 knockdown could be rescued by Gas6 as these cells express both Tyro3 and Axl and hence Axl expression was preserved. An increase in the fraction of Tyro3 knockdown cells in the early apoptotic phase was observed in four different cell lines each with a different TAM expression profile, revealing a broad anti-apoptotic function of Tyro3. Furthermore, in the Tyro3-dependent cells, Tyro3 depletion caused a significant increase in cells in the G0/G1 phase of the cell cycle concomitant with decreases in the G2/M and S phases. In addition, a cancer pathway gene discovery array revealed distinct sets of genes that were altered in expression in cancer cells upon Tyro3 knockdown. Together, these results have elucidated further a role of Tyro3 in promoting multiple tumour-supporting pathways in human cancer cells, which differs in extent depending on the presence of other TAMs in the same cells.

Overexpression of TYRO3 indicates poor prognosis and induces gastric cancer progression via AKT‐mTOR pathway

“…Although TAM family members have no activation mutations promoting cancer development, studies have suggested that the carcinogenic potential of these members is related to abnormal regulation of the TAM receptor signaling pathway 20 . According to previous studies by others, TYRO3 KD did not significantly affect the expression of AXL and MER in several cancer cells 26,28 . Meanwhile, high TYRO3 expression promotes the drug resistance of tumor cells, and targeted therapy for aberrant TYRO3 activation can effectively improve the drug sensitivity of tumor cells 20,29–31 .…”

“…20 According to previous studies by others, TYRO3 KD did not significantly affect the expression of AXL and MER in several cancer cells. 26,28 Meanwhile, high TYRO3 expression promotes the drug resistance of tumor cells, and targeted therapy for aberrant TYRO3 activation can effectively improve the drug sensitivity of tumor cells. 20,[29][30][31] To explore the role of TYRO3 in GC cells, we knocked down TYRO3 expression in GC cell lines and analyzed the changes in the proliferation and migration ability of GC cells.…”

The first laminin G-like domain of protein S is essential for binding and activation of Tyro3 receptor and intracellular signalling

“…Gas6 activates all three TAM receptors, with greatest affinity for Axl followed by Tyro3 then Mer, whereas ProS1 is a ligand for Tyro3 and Mer only [ 11 ]. We have shown that ProS1 is a preferred ligand for Tyro3 over Gas6 in human cancer cells expressing both Tyro3 and Axl receptors [ 30 ], as well as identified Tyro3 signaling pathways that progress the cell cycle and support survival in cancer cells [ 50 ]. However, while there is insight into the structure-function relationships that exist for the Gas6-Axl interaction [ 23 ], no such knowledge exists on the nature of the ProS1-Tyro3 interaction.…”

Novel Substrate Prediction for the TAM Family of RTKs Using Phosphoproteomics and Structure-Based Modeling

“…While their specific role often varies depending on the cellular context, the TAM receptors are typically associated with prosurvival signaling, invasion, and migration. Axl has been implicated in metastasis, migration, invasion, and drug resistance in a number of different cancers. , Mer activity has also been tied to motility and survival signaling under varying contexts. − There are fewer studies on the individual role of Tyro3 compared to Axl and Mer, but despite being understudied, Tyro3 remains an important cancer target as well. − …”