TYRO3
73417892
The Pros1/Tyro3 axis protects against periodontitis by modulating STAT/SOCS signalling
Periodontitis, an oral inflammatory disease caused by periodontal pathogen infection, is the most prevalent chronic inflammatory disease and a major burden on healthcare. The TAM receptor tyrosine kinases (Tyro3, Axl and Mertk) and their ligands (Gas6 and Pros1) play a pivotal role in the resolution of inflammation and have been associated with chronic inflammatory and autoimmune diseases. In this study, we evaluated the effects of exogenous Pros1 in in vitro and in vivo models of periodontitis. We detected higher Pros1 but lower Tyro3 levels in inflamed gingival specimens of periodontitis patients compared with healthy controls. Moreover, Pros1 was mostly localized in the gingival epithelium of all specimens. In cultured human gingival epithelial cells (hGECs) Porphyromonas gingivalis LPS (p.g LPS) stimulation down regulated Pros1 and Tyro3. Exogenous Pros1 inhibited p.g LPS induced production of TNF a, IL 6, IL 1b, MMP9/2 and RANKL in a Tyro3 dependent manner as revealed by PCR, Western blot analysis, ELISA and gelatin zymography. Pros1 also restored Tyro3 expression down regulated by p.g LPS in hGECs. In rats treated with ligature and p.g LPS, administration of Pros1 attenuated periodontitis associated gingival inflammation and alveolar bone loss. Our mechanistic studies implicated SOCS1/3 and STAT1/3 as mediators of the in vitro and in vivo anti inflammatory effects of Pros1. Collectively, the findings from this work supported Pros1 as a novel anti inflammatory therapy for periodontitis.
Journal of cellular and molecular medicine
Lei Jiang Xiao Qing Chen Ming Jing Gao Wai Lee Jie Zhou Yun-fu Zhao Guo Dong Wang
195737563
Live imaging screen reveals that TYRO3 and GAK ensure accurate spindle positioning in human cells
Proper spindle positioning is crucial for spatial cell division control. Spindle positioning in human cells relies on a ternary complex comprising Gai1 3, LGN and NuMA, which anchors dynein at the cell cortex, thus enabling pulling forces to be exerted on astral microtubules. We develop a live imaging siRNA based screen using stereotyped fibronectin micropatterns to uncover components modulating spindle positioning in human cells, testing 1280 genes, including all kinases and phosphatases. We thus discover 16 components whose inactivation dramatically perturbs spindle positioning, including tyrosine receptor kinase 3 (TYRO3) and cyclin G associated kinase (GAK) TYRO3 depletion results in excess NuMA and dynein at the cortex during metaphase, similar to the effect of blocking the TYRO3 downstream target phosphatidylinositol 3 kinase (PI3K) Furthermore, depletion of GAK leads to impaired astral microtubules, similar to the effect of downregulating the GAK interactor Clathrin. Overall, our work uncovers components and mechanisms governing spindle positioning in human cells.Correct spindle positioning is critical for cell division but the full set of proteins regulating this is unclear. Here, with a live imaging siRNA based screen in human cells, the authors identify 16 candidates required for this process, 11 of which were previously unassociated with such a function, including TYRO3 and GAK.
Nature Communications
Benita Wolf Coralie Busso Pierre Gonczy
73433918
TYRO3: A potential therapeutic target in cancer
TYRO3 belongs to the TAM (TYRO3, AXL, and MER) receptor family, a unique subfamily of the receptor tyrosine kinases. Members of TAM family share the same ligand, growth arrest specific 6, and protein S. Although the signal transduction pathways of TYRO3 have not been evaluated in detail, overexpression and activation of TYRO3 receptor tyrosine kinase have been reported to promote cell proliferation, survival, tumorigenesis, migration, invasion, epithelial mesenchymal transition, or chemoresistance in several human cancers. Targeting TYRO3 could break the kinase signaling, stimulate antitumor immunity, reduce tumor cell survival, and regain drug sensitivity. To date, there is no specific TYRO3 targeted drug, the effectiveness of targeting TYRO3 in cancer is worthy of further investigations. In this review, we present an update on molecular biology of TYRO3, summarize the development of potential inhibitors of TAM family members, and provide new insights in TYRO3 targeted treatment. Impact statement Cancer is among the leading causes of death worldwide. In 2016, 8.9 million people are estimated to have died from various forms of cancer. The current treatments, including surgery with chemotherapy and/or radiation therapy, are not effective enough to provide full protection from cancer, which highlights the need for developing novel therapy strategies. In this review, we summarize the molecular biology of a unique member of a subfamily of receptor tyrosine kinase, TYRO3 and discuss the new insights in TYRO3 targeted treatment for cancer therapy.
Experimental biology and medicine
Pei-Ling Hsu Jonathan Jou Shaw-Jenq Tsai
208299036
Oncogenic role of TYRO3 receptor tyrosine kinase in the progression of pancreatic cancer.
The expression and functions of TYRO3, a member of the TAM receptor tyrosine kinase family, in pancreatic cancer (PC) have not been specifically elucidated. In this study, we confirmed TYRO3 expression in five human PC cell lines (PANC 1, MIA PaCa 2, BxPC 3, AsPC 1, and PK 9) using Western blotting. TYRO3 silencing and overexpression studies have revealed that TYRO3 promotes cell proliferation and invasion in PC via phosphorylation of protein kinase B (Akt) and extracellular signal regulated kinase (ERK) Using a mouse xenograft model, we showed that tumor growth was significantly suppressed in mice subcutaneously inoculated with TYRO3 knockdown PC cells compared with mice inoculated with control PC cells. Furthermore, TYRO3 expression was examined in PC tissues obtained from 106 patients who underwent pancreatic resection for invasive ductal carcinoma through immunohistochemical staining. TYRO3 positive patients had poor prognoses for overall survival and disease specific survival compared with TYRO3 negative patients. Multivariate analysis revealed that TYRO3 expression is an independent prognostic factor for overall survival. Our study demonstrates the critical role of TYRO3 in PC progression through Akt and ERK activation and suggests TYRO3 as a novel promising target for therapeutic strategies against PC.
Cancer letters
Masaki Morimoto Yosuke Horikoshi Kazuhiro Nakaso Tatsuyuki Kurashiki Yoshinori Kitagawa Takehiko Hanaki Teruhisa Sakamoto Soichiro Honjo Yoshihisa Umekita Yoshiyuki Fujiwara Tatsuya Matsura
209341766
Functional Genomics Identifies Hepatitis Induced STAT3 TYRO3 STAT3 Signaling as a Potential Therapeutic Target of Hepatoma
Purpose: Hepatitis promotes the development and recurrence of hepatocellular carcinoma (HCC) Receptor tyrosine kinases (RTK) play critical roles in the development of many cancers. We explored the potential roles of RTKs in hepatitis related liver cancers. Experimental Design: We conducted loss of function screening to elucidate the roles of RTKs in the development of HCC in vitro and in vivo. Results: Many RTKs were coexpressed in HCC and were involved in tumor development and growth. Of these, TYRO3 promoted tumor growth and was clinically associated with hepatitis activity and poor prognosis. In mice, chemical induced hepatitis transcriptionally activated Tyro3 expression via IL 6/IL6R STAT3 signaling. Moreover, hepatitis associated apoptotic cells facilitated the presentation of GAS6, a TYRO3 ligand, to further activate TYRO3 mediated signaling. Furthermore, TYRO3 activation elicited intracellular SRC and STAT3 signaling. In mice, hepatitis and Tyro3 synergistically promoted HCC development. Silencing TYRO3 expression or inhibiting its kinase activity suppressed xenograft HCC growth in nude mice. Conclusions: Many RTKs are simultaneously involved in HCC development. Hepatitis exerts dual effects on the activation of TYRO3 mediated signaling in HCC cells, which further elicits the "TYRO3 STAT3 TYRO3" signaling loop to facilitate tumor growth. Our findings unveil a previously unrecognized link between RTKs and hepatitis associated HCC and suggest TYRO3 as a marker and therapeutic target for the HCCs with higher hepatitis activity.
Clinical Cancer Research
Chia-Liang Tsai Jeng-Shou Chang Ming-Chin Yu Chern-Horng Lee Tse-Ching Chen Wen-Yu Chuang Wei-Liang Kuo Chen-Chun Lin Shi-Ming Lin Sen-Yung Hsieh
196514962
THU0054 THE SYNOVIAL FLUID FROM RHEUMATOID ARTHRITIS PATIENTSCONTAINS SOLUBLE TAM RECEPTOR TYROSINE KINASES OF WHICH SOLUBLE TYRO3 AND ITS LIGAND GAS6 CORRELATES WITH THE PROINFLAMMATORY CYTOKINE LEVELS
Background We recently showed that the tyrosine protein kinase receptors MER and AXL, both members of the TAM (including TYRO3) receptor family, play a protective role in mouse models of rheumatoid arthritis (RA) [1, 2] In both humans and mice, TAM receptors can be proteolytically cleaved from the cell membrane and shed as a soluble (s) receptors. These sTAM receptors may act as decoy receptors, bind their ligands Growth Arrest Specific 6 (GAS6) and Protein S (PROS1) and thereby inhibit the immunoregulatory and anti inflammatory effect of TAM receptor activation, and prevent TAM receptor mediated phagocytic clearance of dying cells. Objectives To determine the soluble TAM receptor levels in synovial fluids from RA and osteoarthritis (OA) patients and correlate this to the inflammatory process. Methods The level of sMER, sAXL, sTYRO3, GAS6, IL 8, TNFa and IL 1b was measured in synovial fluids of RA (n 28) and OA patients (n 12) by ELISA or multiplex array. Synovial explants were cultured for 24 hrs and the release of sMER and GAS6 was measured by ELISA. Human synovial explants of RA (n 15) and osteoarthritis (OA) (n 17) patients were immunostained for MER. Results Soluble MER and sTYRO3 were significantly enhanced in synovial fluids (P<0.0001 and P=0.0042) of RA patients as compared to OA patients. The sAXL and GAS6 levels in synovial fluid of RA and OA patients was equally high (P 0.267 and P 0.074) In RA patients, but not in OA patients, the synovial fluid levels of sTYRO3 and GAS6 (a ligand for all three TAM receptors) positively correlated with TNFa (r=0.555, r=0.477) IL 1b (r=0.597, r=0.481) and IL 8 (r=0.567, r=0.529) Soluble MER levels, however, did not correlated with local inflammatory markers. Although synovial explants from RA released more sMER into the culture media than explants from OA (P 0.0045) the explants of both RA and OA patients contained comparable amounts of immunopositive MER cells. Conclusion We showed that synovial fluid sTYRO3 and GAS6 levels correlates with higher proinflammatory cytokine levels in RA but not in OA patients. This is in line with the recent observation done by Xu et al. [3] that circulating levels of sTYRO3, but not sMER or sAXL, correlates with disease activity and bone destruction in RA patients. In accordance to serum, the synovial sMER levels were significantly higher in RA than in OA patients with sAXL levels comparable between both patient groups. Interestingly, only for sMER the synovial fluid levels were much higher than in serum suggesting local production as we confirmed in the synovial explants cultures. This illustrates that release of soluble TAM receptors is either the results of different processes (enzymatic shedding or alternative splicing isoforms) or reflects the different cell populations in the arthritic joint. We found that naive macrophages express high MER and inducible AXL, while synovial fibroblast express high AXL and TYRO3. Further studies are warranted to determine if sMER levels impair the clearance of apoptotic cells in the arthritic joint as we have found in our mice studies. Our study shows that synovial sTYRO3 is a marker for joint inflammation and possibly a novel therapeutic target for RA. References [1] Waterborg, C.E. et al. Protective role of the Mer Tyrosine Kinase via efferocytosis in rheumatoid arthritis Models. Frontiers in immunology, 2018. 9. [2] Waterborg, C.E. et al. 03.05 The tam receptors axl and mer play a protective role in a temporal and spatial manner in inflammatory arthritis. 2017, BMJ Publishing Group Ltd. [3] Xu, L. et al. Soluble TAM receptor tyrosine kinases in rheumatoid arthritis: correlation with disease activity and bone destruction. Clinical Experimental Immunology, 2018. 192(1) p. 95 103. Disclosure of Interests None declared
Poster Presentations
Julia Vullings Claire E J Waterborg Marije I Koenders P L van Lent Peter M Kraan Fons van de Loo
219268046
Abstract 2638: Galectin 3 activates the receptor tyrosine kinase Tyro3 and stimulates ERK signaling, cell survival and migration in human head and neck cancer cells
The beta galactoside binding protein galectin 3 (Gal 3) has been shown to influence the tumorigenic behaviour of cancer cells, and elevated serum levels of Gal 3 have been linked to tumor metastasis in several different cancers. Previously, Gal 3 was shown to be a ligand MerTK, a member of the TAM (Tyro3, Axl, MerTK) subfamily of receptor tyrosine kinases (RTKs) these RTKs are implicated in tumorigenesis and/or enabling tumor chemoresistance in many different cancers. However, it is not known whether Gal 3 is also a ligand for the other two TAM RTKs, nor what signaling pathways it activates to regulate cancer cell functions. This study is aimed at determining the ligand properties of Gal 3 against Tyro3 and Axl RTKs in human cancer cells and the oncogenic signal pathways linked to them. The cultured human head and neck squamous cell carcinoma (HNSCC) cell line SCC 25 was determined by western blot and qPCR to express both Axl and Tyro3, but not MerTK. Recombinant Gal 3 and the TAM ligands Gas6 and ProS1 were added to serum starved cells over a time period of minutes and cells lysed to determine activation/phosphorylation of RTKs and intracellular signal mediators by western blotting. Longer incubations were performed to measure cell viability (MTS assay) and cell migration rate (scratch assay) All experiments were carried out a minimum three times. The known TAM ligands Gas6 and ProS1 stimulated TAM RTKs differentially in SCC 25 cells: Gas6 activated Axl strongly within minutes, with ProS1 having a weak effect. In contrast, ProS1 was the strongest ligand for Tyro3, activating it by fourfold, followed by Gal 3 at threefold and Gas6 at twofold. All three exogenous proteins also rapidly stimulated ERK1/2 phosphorylation by two fold, whereas only Gas6 and Gal 3 stimulated Akt phosphorylation. All three proteins significantly maintained cell survival during acute induction of apoptosis by staurosporine. However, only Gas6 conferred a survival effect over long term serum starvation induced cell death. In addition, Gal 3 significantly stimulated cell migration during Axl blockade with the small molecule Axl inhibitor BGB324, further suggesting a role for Tyro3 in this effect. These results have shown that Gal 3 is a ligand for Tyro3 RTK, and that Gal 3 promotes cell survival and migration in HNSCC cells, coupled with activation of both the related signal pathways ERK and Akt. The data therefore reveal a new mechanism of Tyro3 activation; however, it remains to be determined whether Gal 3 interacts with the glycosyl chain on the RTK or else via other interfaces. Finally, cancer therapeutic strategies targeting Gal 3 action and/or cell surface glycosylation may be viable approaches in further research. Citation Format: Sassan Hafizi, Nour Al Kafri. Galectin 3 activates the receptor tyrosine kinase Tyro3 and stimulates ERK signaling, cell survival and migration in human head and neck cancer cells [abstract] In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29 Apr 3; Atlanta, GA. Philadelphia (PA) AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2638.
Molecular and Cellular Biology Genetics
Sassan Hafizi N Kafri
198301010
Abstract 2879: TYRO3 is a potential therapeutic target in pediatric acute myeloid leukemia
BACKGROUND: While outcomes for children with acute myeloid leukemia have improved dramatically in recent years, a subset of patients continue to have poor prognosis with METHODS: The TARGET database was utilized to determine expression of mRNAs encoding the TAM family kinases and their ligands, GAS6 and PROS1, in pediatric AML patient samples. Samples (n=145) were categorized into two groups with "high" expression greater than the median or "low" expression less than or equal to the median and overall survival was compared between the two groups using the log rank test. Expression of TAM family kinases and ligands was determined in AML cell lines by immunoblot. Derivatives of the NB4 AML cell line with shRNA mediated inhibition of TYRO3 were generated and the impact of TYRO3 inhibition on MERTK levels was determined by immunoblot. RESULTS: High levels of TYRO3 or PROS1 mRNAs in patient samples were independently associated with decreased overall survival in children with AML (p CONCLUSIONS: TYRO3 was ubiquitously expressed in all AML cell lines tested and higher levels of TYRO3 and its ligand PROS1 were associated with significantly poorer prognosis in children with AML. These data suggest a role for TYRO3 in pediatric AML and implicate TYRO3 as a therapeutic target in this context. Citation Format: Sherri K. Smart, Manali Rupji, Bhakti Dwivedi, Jeanne Kowalski, Deborah DeRyckere, Douglas K. Graham. TYRO3 is a potential therapeutic target in pediatric acute myeloid leukemia [abstract] In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29 Apr 3; Atlanta, GA. Philadelphia (PA) AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2879.
Sherri K Smart Manali Rupji Bhakti Dwivedi Jeanne Kowalski Deborah DeRyckere Douglas Kim Graham
54558567
The Emerging Role of TYRO3 as a Therapeutic Target in Cancer
The TAM family (TYRO3, AXL, MERTK) tyrosine kinases play roles in diverse biological processes including immune regulation, clearance of apoptotic cells, platelet aggregation, and cell proliferation, survival, and migration. While AXL and MERTK have been extensively studied, less is known about TYRO3. Recent studies revealed roles for TYRO3 in cancer and suggest TYRO3 as a therapeutic target in this context. TYRO3 is overexpressed in many types of cancer and functions to promote tumor cell survival and/or proliferation, metastasis, and resistance to chemotherapy. In addition, higher levels of TYRO3 expression have been associated with decreased overall survival in patients with colorectal, hepatocellular, and breast cancers. Here we review the physiological roles for TYRO3 and its expression and functions in cancer cells and the tumor microenvironment, with emphasis on the signaling pathways that are regulated downstream of TYRO3 and emerging roles for TYRO3 in the immune system. Translational agents that target TYRO3 are also described.
Cancers
Sherri K Smart Eleana Vasileiadi Xiaodong Wang Deborah DeRyckere Douglas Kim Graham
196567338
PF245 METFORMIN INHIBITS THE GROWTH OF MYELOID LEUKEMIA CELLS PARTLY DUE TO SUPPRESSION OF TYRO3 EXPRESSION
HemaSphere
T Saito Mai Itoh Shuji Tohda