Transforming activity of receptor tyrosine kinase Tyro3 is mediated, at least in part, by the PI3 kinase-signaling pathway

Abstract

Protein tyrosine phosphorylation is an integral part of cytokine-induced proliferation and differentiation of hematopoietic cells. The authors previously reported cloning and characterization of the receptor tyrosine kinase Tif, also termed Tyro3. Using the yeast 2-hybrid technology, they recently identified that the p85 subunit of phosphatidylinositol 3-kinase (PI3 kinase) interacted with the cytoplasmic domain of Tyro3. On treatment with epidermal growth factor (EGF), NIH3T3 cells expressed EGFR/Tyro3 (a fusion receptor with the extracellular domain from epidermal growth factor receptor and the transmembrane and cytoplasmic domains from Tyro3), and EGFR/Tyro3 was rapidly phosphorylated on tyrosine residues. The interaction between Tyro3 and p85 was also confirmed by glutathione S-transferase (GST) pull-down experiments. Co-immunoprecipitation followed by Western blot analysis revealed that PI3 kinase was associated with and phosphorylated by the activated Tyro3. Tyro3-associated PI3 kinase exhibited an enhanced kinase activity. In addition, EGF treatment of EGFR/Tyro3-expressing cells led to enhanced phosphorylation of Akt, a downstream component of PI3 kinase. Treatment of NIH3T3 cells expressing a full length of rat Tyro-3, but not NIH3T3 cells, with protein S also resulted in phosphorylation of Akt. Soft agar colony assays showed that the addition of EGF to EGFR/Tyro3-transfected cells, but not to the parental NIH3T3 cells, resulted in a concentration-dependent increase in the formation of anchorage-independent colonies. Tyro3-mediated transformation of NIH3T3 cells was significantly blocked by wortmannin, a PI3 kinase-specific inhibitor. Results of these combined studies strongly suggested that the oncogenic transforming ability of Tyro3 was mediated at least in part by the PI3 kinase pathway.

A microRNA‐7/growth arrest specific 6/TYRO3 axis regulates the growth and invasiveness of sorafenib‐resistant cells in human hepatocellular carcinoma

“…TYRO3 is reported to modulate several oncogenic pathways, including survival, altered cellular morphology, cell‐cycle transition, proliferation, adhesion, motility, and release of a number of inflammatory cytokines and is observed elevated in 42% of HCC cases . It is also known to induce neoplastic transformation in nonmalignant cells and becomes activated in dormant tumors about to proliferate . In the presence of limited therapeutic options for patients with HCC, TYRO3 represents a promising option for developing new HCC‐targeted drug therapies.…”

Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases

“…In addition to suggesting a role for Sky in neurotrophism, Sky is also expressed in osteoclasts in bone, indicating a role in bone resorption [27]. Although able to induce cell transformation experimentally [28], information on the status of Sky expression in human cancer is scant. Sky has been detected in several human leukaemic cell lines and blasts of acute myeloid leukaemia patients [29], and overexpressed in myeloma cells compared to autologous Blymphoblastoid cell lines [30].…”

“…Like Axl, Sky also responds to ligand stimulation as a true receptor and is activated by Gas6 in a matter of minutes [27]. The p85 subunit of PI3K has also been detected in a yeast two-hybrid screen as a binding partner for Sky, and stimulation with human protein S activates rat Sky to induce PI3K and Akt activation [28]. In bone, Gas6 has been shown to stimulate mouse osteoclastic bone resorption via Sky, involving activation of ERK [95].…”

Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma

“…In contrast, 1 kinase, ROR2, was commonly phosphorylated across all 3 cell lines. To confirm whether or not Tyro3 expression affects the activity of a downstream substrate in PEL cells, we examined if phosphorylation of the p85 regulatory subunit of PI3K, a known substrate of Tyro3, was affected upon knockdown of Tyro3 (43). We tested several short-hairpin (sh)RNA constructs against Tyro3 in PEL (BCBL1 and BC1) and DLBCL BJAB cells (SI Appendix, Fig.…”