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Predicting the Specificity- Determining Positions of Receptor Tyrosine Kinase Axl.

ABSTRACT: Owing to its clinical significance, modulation of functionally relevant amino acids in protein-protein complexes has attracted a great deal of attention. To this end, many approaches have been proposed to predict the partner-selecting amino acid positions in evolutionarily close complexes. These approaches can be grouped into sequence-based machine learning and structure-based energy-driven methods. In this work, we assessed these methods' ability to map the specificity-determining positions of Axl, a receptor tyrosine kinase involved in cancer progression and immune system diseases. For sequence-based predictions, we used SDPpred, Multi-RELIEF, and Sequence Harmony. For structure-based predictions, we utilized HADDOCK refinement and molecular dynamics simulations. As a result, we observed that (i) sequence-based methods overpredict partner-selecting residues of Axl and that (ii) combining Multi-RELIEF with HADDOCK-based predictions provides the key Axl residues, covered by the extensive molecular dynamics simulations. Expanding on these results, we propose that a sequence-structure-based approach is necessary to determine specificity-determining positions of Axl, which can guide the development of therapeutic molecules to combat Axl misregulation.

SUBMITTER: Karakulak T

PROVIDER: S-EPMC8236827 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Axl receptor tyrosine kinase expression in breast cancer.

Project description:AimsTriple-negative breast cancer comprises a clinically aggressive group of invasive carcinomas. We examined a published gene expression screen of a panel of breast cancer cell lines to identify a potential triple-negative breast cancer-specific gene signature, and attempted to verify our findings by performing immunohistochemical analysis on tissue microarrays containing a large cohort of invasive breast carcinomas.MethodsThe microarray dataset for a panel of human breast cancer cell lines was interrogated for triple-negative breast cancer-specific genes. Membranous immunohistochemical expression of the protein product of the AXL gene was assessed semiquantitatively in 569 invasive breast carcinomas grouped according to molecular subgroup by immunohistochemistry.ResultsAXL was significantly upregulated in triple-negative/basal B cell lines compared with luminal or basal A cell lines. No significant difference was observed in the level of immunohistochemical expression of Axl protein between triple-negative breast cancers and other molecular subgroups (p=0.257). Axl expression was significantly associated with lymphovascular invasion (LVI) in all subgroups combined (p=0.033), and within the luminal A (p=0.002) and triple-negative breast cancer subgroups (p=0.026).ConclusionsDespite preferential upregulation of AXL in triple-negative/basal B cell lines, analysis of Axl protein expression in a large series of patients' breast tumours revealed no association between Axl expression and triple-negative breast cancer or other subtype. The association of Axl expression with LVI supports previous work that implicates Axl as a promoter of invasiveness in breast cancer cell lines. Further studies are necessary to explore whether Axl expression of individual breast cancer tumours can be clinically useful.

| S-EPMC4549806 | biostudies-literature

Quantitative Tyrosine Phosphoproteome Profiling of AXL Receptor Tyrosine Kinase Signaling Network.

Project description:Overexpression and amplification of AXL receptor tyrosine kinase (RTK) has been found in several hematologic and solid malignancies. Activation of AXL can enhance tumor-promoting processes such as cancer cell proliferation, migration, invasion and survival. Despite the important role of AXL in cancer development, a deep and quantitative mapping of its temporal dynamic signaling transduction has not yet been reported. Here, we used a TMT labeling-based quantitative proteomics approach to characterize the temporal dynamics of the phosphotyrosine proteome induced by AXL activation. We identified >1100 phosphotyrosine sites and observed a widespread upregulation of tyrosine phosphorylation induced by GAS6 stimulation. We also detected several tyrosine sites whose phosphorylation levels were reduced upon AXL activation. Gene set enrichment-based pathway analysis indicated the activation of several cancer-promoting and cell migration/invasion-related signaling pathways, including RAS, EGFR, focal adhesion, VEGFR and cytoskeletal rearrangement pathways. We also observed a rapid induction of phosphorylation of protein tyrosine phosphatases, including PTPN11 and PTPRA, upon GAS6 stimulation. The novel molecules downstream of AXL identified in this study along with the detailed global quantitative map elucidating the temporal dynamics of AXL activation should not only help understand the oncogenic role of AXL, but also aid in developing therapeutic options to effectively target AXL.

| S-EPMC8394654 | biostudies-literature

AXL receptor tyrosine kinase as a therapeutic target in NSCLC.

Project description:The AXL receptor tyrosine kinase and its ligand, Gas6, regulate key processes in lung cancer growth, metastasis, and epithelial-mesenchymal transition-associated drug resistance. Gas6 and AXL expression have been correlated with poor prognosis and advanced clinical stage in patients with lung cancer, and targeting the Gas6/AXL pathway demonstrates antitumor activity, decreases cellular invasion, and restores sensitivity in de novo and acquired drug resistance models. These findings implicate AXL as a promising therapeutic target in lung cancer. In this review, we explore the role of AXL in lung cancer progression, from tumor development to disseminated disease, and highlight the current clinical landscape of anti-AXL therapeutics.

| S-EPMC5217513 | biostudies-literature

Implications of the Receptor Tyrosine Kinase Axl in Gastric Cancer Progression.

Project description:Background:Gastric cancer (GC) is an aggressive malignancy with high lethality. Systematic chemotherapy is the main therapeutic strategy for advanced GC patients. The overexpression of Axl is associated with poor prognosis and regulates tumor growth and metastasis in many types of cancer. However, the role of Axl in GC progression remains elusive. Materials and Methods:Western blot and quantitative real-time PCR assay (RT-PCR) assays were used to detect the expression of Gas6, Axl, ZEB1 and epithelial-mesenchymal transition (EMT)-related markers in GC cells. Cell proliferation was determined by EdU cell proliferation assay and CCK-8 assay. Transwell invasion assay was performed to explore the effect of Axl and ZEB1 on cell invasion. Tumor xenografts and lung metastasis models were conducted to examine the effect of Axl on the growth and lung metastasis of GC cells. Results:In our study, we found that high levels of Gas6 and Axl expression were associated with reduced overall survival (OS) in GC patients and the expression of Gas6 and Axl was upregulated in GC cell lines. Ectopic expression of Axl induced EMT and promoted GC cell invasion and proliferation. The knockdown of Axl inhibited EMT and suppressed the proliferation and invasion of GC cell. In vivo study showed that inhibition of Axl impaired tumor growth and lung metastasis of GC cells. Mechanistic investigations revealed that Axl promoted EMT, invasion, and proliferation via upregulating ZEB1 expression in GC cells. Conclusion:Our results demonstrated that the Gas6/Axl/ZEB1 signaling pathway regulated EMT, invasion, and proliferation in GC cells and might represent a potential therapeutic target for GC treatment.

| S-EPMC7319943 | biostudies-literature

Inhibition of AXL Receptor Tyrosine Kinase Enhances Brown Adipose Tissue Functionality in mice.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-06-22 | GSE231471 | GEO

The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer.

Project description:The receptor tyrosine kinases (RTKs) TYRO3, AXL and MERTK (TAM) have well-described oncogenic functions in a number of cancers. Notwithstanding, TAM RTKs are also potent and indispensable inhibitors of inflammation. The combined deletion of Axl and Mertk in mice enhances chronic inflammation and autoimmunity, including increased inflammation in the gut and colitis-associated cancer. On the other hand, deletion of Tyro3 increases the risk of allergic responses. Therefore, the indiscriminate inhibition of these TAM RTKs could result in undesirable immunological diseases. Here we show that AXL, but not MERTK or TYRO3 expression is enhanced in late stage colorectal cancer (CRC) and AXL expression associates with a cell migration gene signature. Silencing AXL or the inhibition of AXL kinase activity significantly inhibits tumor cell migration and invasion. These results indicate that the selective inhibition of AXL alone might confer sufficient therapeutic benefit in CRC, while preserving at least some of the beneficial, anti-inflammatory effects of MERTK and TYRO3 RTKs.

| S-EPMC5519024 | biostudies-literature

Molecular analysis of alternative transcripts of equine AXL receptor tyrosine kinase gene.

Project description:OBJECTIVE:Since athletic performance is a most importance trait in horses, most research focused on physiological and physical studies of horse athletic abilities. In contrast, the molecular analysis as well as the regulatory pathway studies remain insufficient for evaluation and prediction of horse athletic abilities. In our previous study, we identified AXL receptor tyrosine kinase (AXL) gene which was expressed as alternative spliced isoforms in skeletal muscle during exercise. In the present study, we validated two AXL alternative splicing transcripts (named as AXLa for long form and AXLb for short form) in equine skeletal muscle to gain insight(s) into the role of each alternative transcript during exercise. METHODS:We validated two isoforms of AXL transcripts in horse tissues by reverse transcriptase polymerase chain reaction (RT-PCR), and then cloned the transcripts to confirm the alternative locus and its sequences. Additionally, we examined the expression patterns of AXLa and AXLb transcripts in horse tissues by quantitative RT-PCR (qRT-PCR). RESULTS:Both of AXLa and AXLb transcripts were expressed in horse skeletal muscle and the expression levels were significantly increased after exercise. The sequencing analysis showed that there was an alternative splicing event at exon 11 between AXLa and AXLb transcripts. 3-dimentional (3D) prediction of the alternative protein structures revealed that the structural distance of the connective region between fibronectin type 3 (FN3) and immunoglobin (Ig) domain was different between two alternative isoforms. CONCLUSION:It is assumed that the expression patterns of AXLa and AXLb transcripts would be involved in regulation of exercise-induced stress in horse muscle possibly through an NF-?B signaling pathway. Further study is necessary to uncover biological function(s) and significance of the alternative splicing isoforms in race horse skeletal muscle.

| S-EPMC5582333 | biostudies-literature

AXL receptor tyrosine kinase: a possible therapeutic target in acute promyelocytic leukemia.

Project description:BackgroundAcute promyelocytic leukemia (APL) is a subset of acute myeloid leukemia (AML) which is characterized by the fusion of promyelocytic leukemia PML and retinoic acid receptor- alpha (RAR-alpha) genes. All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) have resulted in durable cytogenetic and molecular remissions in most APL patients and have altered the natural history of the disease. Most APL patients treated with ATRA and/or ATO are now anticipated to have a nearly normal life expectancy. Unfortunately, relapse and resistance to the current treatment occur in APL patients and the outcome remains dismal in these refractory patients. AXL receptor tyrosine kinase (AXL-RTK) has been shown to increase tumour burden, provide resistance to therapy and is critical to maintain cancer stem cells (CSCs) in chronic myeloid leukemia (CML) by stabilizing β-catenin in the Wnt/β-catenin signalling pathway. However, the role of AXL-RTK has not been explored in PML/RARα-positive APL. This study aimed to explore the role of AXL-RTK receptor in PML/RARα-positive APL.Methods and resultsBy using biochemical and pharmacological approaches, here we report that targeting of AXL-RTK is related to the down-regulation of β-catenin target genes including c-myc (p < 0.001), AXIN2 (p < 0.001), and HIF1α (p < 0.01) and induction of apoptosis in PML/RARα-positive APL cell line. Resistance to all-trans retinoic acid (ATRA) was also overcomed by targeting AXL-RTK with R428 in APL (p < 0.05).ConclusionOur results provide clear evidence of the involvement of AXL-RTK in leukemogenic potential of PML/RARα-positive APL and suggest targeting of AXL-RTK in the treatment of therapy resistant APL patients.

| S-EPMC8210361 | biostudies-literature

Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction.

Project description:Tyro3, AXL, and MerTK (TAM) receptors are activated in macrophages in response to tissue injury and as such have been proposed as therapeutic targets to promote inflammation resolution during sterile wound healing, including myocardial infarction. Although the role of MerTK in cardioprotection is well characterized, the unique role of the other structurally similar TAMs, and particularly AXL, in clinically relevant models of myocardial ischemia/reperfusion infarction (IRI) is comparatively unknown. Utilizing complementary approaches, validated by flow cytometric analysis of human and murine macrophage subsets and conditional genetic loss and gain of function, we uncover a maladaptive role for myeloid AXL during IRI in the heart. Cross signaling between AXL and TLR4 in cardiac macrophages directed a switch to glycolytic metabolism and secretion of proinflammatory IL-1β, leading to increased intramyocardial inflammation, adverse ventricular remodeling, and impaired contractile function. AXL functioned independently of cardioprotective MerTK to reduce the efficacy of cardiac repair, but like MerTK, was proteolytically cleaved. Administration of a selective small molecule AXL inhibitor alone improved cardiac healing, which was further enhanced in combination with blockade of MerTK cleavage. These data support further exploration of macrophage TAM receptors as therapeutic targets for myocardial infarction.

| S-EPMC7954597 | biostudies-literature

RETRACTED: The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor.

Project description:The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance. Cetuximab-resistant clones of non-small cell lung cancer in culture and patient-derived xenografts in mice had increased abundance of AXL and nuclear EGFR (nEGFR). Cellular fractionation analysis, super-resolution microscopy, and electron microscopy revealed that genetic loss of AXL reduced the accumulation of nEGFR. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. We found that AXL knockdown reduced the expression of the genes encoding the SFK family members YES and LYN and the ligand neuregulin-1 (NRG1). AXL knockdown also decreased the interaction between EGFR and the related receptor HER3 and accumulation of HER3 in the nucleus. Overexpression of LYN and NRG1 in cells depleted of AXL resulted in accumulation of nEGFR, rescuing the deficit induced by lack of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK and NRG1 expression promote this process.

| S-EPMC7094775 | biostudies-literature

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