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Новая потенциальная ось лиганда-рецептора, связанная с ремонтом тканей в качестве терапевтических целей в прогрессивном множественном склерозе.

Прогрессивный множественный склероз (MS) представляет собой ухудшающуюся фазу заболевания, характеризующуюся увеличением нейродегенерации и инвалидностью и главным образом отказом от текущего лечения. Поиск вариантов лечения по-прежнему сопряжен с определенными трудностями не только из-за отсутствия понимания патогенных механизмов, но и из-за того, что ранние догмы были сосредоточены на нейроинфламмации, что затмевало важнейшую роль процесса ремонта тканей. Цель по ремонту тканей должна начинаться на раннем этапе развития болезней, а терапевтические стратегии для прогрессивных MS должны сочета

Совпадение в аннотации оригинала
Progressive multiple sclerosis (MS) represents the worsening phase of the disease, characterized by increasing neurodegeneration and disabil … h as growth-arrest-specific 6 (GAS6)/protein tyrosine kinase receptor (TYRO3) and protein S (PROS1)/AXL receptor tyrosine kinase (AXL), required to dampen inflammation, promote tissue repair, and engage remyelination. Understanding the role of these proteins in the early stages of MS is a critical step toward preventing or stopping neurodegeneration. Herein, we will discuss t …

Receptor-Ligand Biomarker Profile in Ankylosing Spondylitis: Associations Between AXL/MERTK Expression, Circulating GAS6 and Protein S Levels, and Disease Activity.

(1) Background: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease associated with immune dysregulation. The TYRO3, AXL, and MER (TAM) signaling pathway, comprising AXL receptor tyrosine kinase (AXL), MER tyrosine kinase (MERTK), growth arrest-specific 6 (GAS6), and Protein S, is a key regulator of immune homeostasis. This study investigated these receptor-ligand components in patients with AS. (2) Methods: A total of 45 patients with AS and 44 healthy controls were enrolled. Serum GAS6 and Protein S levels were measured by ELISA, and AXL and MERTK expression levels were a…

Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells.

In this study, we have addressed how Lyn kinase signaling mediates nilotinib-resistance by quantitative phospho-proteomics using Stable Isotope Labeling with Amino acid in Cell culture. We have found an increased tyrosine phosphorylation of 2 additional tyrosine kinases in nilotinib-resistant cells: the spleen tyrosine kinase Syk and the UFO family receptor tyrosine kinase Axl. This increased tyrosine phosphorylation involved an interaction of these tyrosine kinases with Lyn. Inhibition of Syk by the inhibitors R406 or BAY 61-3606 or by RNA interference restored the capacity of nilotinib to in

SFTSV utilizes AXL/GAS6 for entry via PI3K-PLC-dependent macropinocytosis activated by AXL-kinase.

Severe fever with thrombocytopenia syndrome (SFTS) is a significant public health concern caused by SFTS virus (SFTSV), a tick-borne RNA virus. Previous studies have identified DC-SIGN and related C-type lectins as receptors of SFTSV infection in specific cell populations. Our genome-wide CRISPR activation screening identified AXL, a receptor tyrosine kinase, as a novel entry receptor for SFTSV. We found that AXL-mediated SFTSV infection utilizes the bridging action of growth arrest-specific protein 6 between AXL and phosphatidylserine on virus particles. This interaction induces autophosphory

High-throughput high-content imaging assays for identification and characterization of selective AXL pathway inhibitors.

Receptor tyrosine kinases (RTKs) regulate a wide range of important biological activities, including cell proliferation, differentiation, migration, and apoptosis. Abnormalities in RTKs are involved in numerous diseases, including cancer and other proliferative disorders. AXL belongs to the TAM (Tyso3, AXL, and Mer) family of RTKs. The AXL signaling pathway represents an attractive target for the treatment of diseases, such as cancer. Using phospho-AKT as readout, a high-throughput 384-well cell-based assay was established in the NCI-H1299 human non-small cell lung carcinoma cell line to evalu

Axl Blockade by BGB324 Inhibits BCR-ABL Tyrosine Kinase Inhibitor-Sensitive and -Resistant Chronic Myeloid Leukemia.

Purpose: BCR-ABL kinase inhibitors are employed successfully for chronic myeloid leukemia (CML) treatment. However, resistant disease and pe … we also investigated BGB324 in combination with imatinib.Results: We demonstrate overexpression of Axl receptor tyrosine kinase in primary cells of patients with CML compared with healthy individuals and a further increase of Axl expression in BCR-ABL TKI-resistant patients. We show that Axl blockage decreased growth of BCR-ABL TKI-sensitive CML cells including CD34+ cells a …

Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling, which progressively abolishes lung function in an RTK (receptor tyrosine kinase)-dependent manner. Gas6 (growth arrest-specific 6) ligand, Tyro3 (TYRO3 protein tyrosine kinase 3), and Axl (anexelekto) RTK expression and activity are increased in IPF. OBJECTIVES: To determine if targeting these RTK pathways would inhibit fibroblast activation and the development of pulmonary fibrosis. METHODS: Quantitative genomic, proteomic, and functional analyses were used to determine Gas6/TAM (Tyro3, Axl, and Mer

AXL at the nexus of therapeutic resistance, tumor vascularization, and immune evasion in cancer.

AXL, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinase family, has emerged as a high-priority therapeutic target in oncology. Unlike canonical oncogenic kinase drivers, AXL activation is rarely attributable to direct genetic alterations but instead arises through adaptive, non-genetic mechanisms including hypoxia, inflammation, epithelial-to-mesenchymal transition, and therapeutic selection pressure. In this review, we synthesize the current understanding of AXL biology and the translational opportunities for AXL inhibition across multiple malignancies, with a focus on gliob

Identification of AXL as a co-receptor for human parvovirus B19 infection of human erythroid progenitors.

Parvovirus B19 (B19V) infects human erythroid progenitor cells (EPCs) and causes several hematological disorders and fetal hydrops. Amino acid (aa) 5-68 of minor capsid protein VP1 (VP1u5-68aa) is the minimal receptor binding domain for B19V to enter EPCs. Here, we carried out a genome-wide CRISPR-Cas9 guide RNA screen and identified tyrosine protein kinase receptor UFO (AXL) as a proteinaceous receptor for B19V infection of EPCs. AXL gene silencing in ex vivo expanded EPCs remarkably decreased B19V internalization and replication. Additions of the recombinant AXL extracellular domain or a pol

Magnolol suppresses TKI-resistant EGFR-mutant lung cancer by inhibiting EGFR and AXL-cMyc.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, remains a major th … t of mutant EGFR, accompanied by reduced EGFR phosphorylation. In addition, magnolol suppressed the AXL receptor tyrosine kinase (AXL)-cMyc signaling axis and impaired homologous recombination repair by downregulating Rad51, leading to accumulation of DNA damage. These effects were enhanced when combined with brigatinib, a clinically approved multi-kinase inhibitor with activ …

AXL phosphosite mapping links FAK1 and YAP1 signaling to erlotinib resistance in EGFR-mutant lung cancer.

Targeted therapies for receptor tyrosine kinases are effective but invariably limited by drug resistance. In EGFR-mutant lung cancer, AXL activation drives resistance to erlotinib by restoring cell survival and migration. To map these signaling mechanisms, we generated a panel of lung adenocarcinoma PC9 cell lines with phenylalanine substitutions at each intracellular AXL tyrosine residue. By integrating phosphorylation data with phenotypic changes via multivariate modeling, we found that AXL signaling organizes into two clusters enriched for Abl1 and SFK substrate motifs. A peptide specificit

1D228 Attenuates Sorafenib Resistance in Renal Cell Carcinoma Models by Dual Targeting c-Met and AXL.

Sorafenib is widely used to treat metastatic renal cell carcinoma (RCC); however, the acquired drug resistance limits its efficacy and application in clinical practice. The receptor tyrosine kinases c-Met and AXL play important roles in cancer progression and are involved in tyrosine kinase inhibitor-induced drug resistance in cancers, but whether these two receptors also contribute to sorafenib-induced drug resistance in RCC is unclear. In this study, we evaluated our synthesized compound 1D228, a TKI derived from Tepotinib, in sorafenib-resistant RCC models, which demonstrated further inhibi

Breaking resistance in BRAF-mutant Melanoma: Novel strategies and biomarkers for optimizing targeted therapies.

In metastatic melanoma with a BRAFV600 mutation, inhibitors of BRAF and MEK have improved survival. Resistance may be acquired through late genetic alterations that restore mitogen-activated protein kinase (MAPK) signaling. Resistance can also be adaptive, involving early and reversible transcriptional or metabolic shifts that generate drug-tolerant cells, or intrinsic, arising from pre-existing conditions such as phosphatase and tensin homolog (PTEN) loss or an AXL receptor tyrosine kinase-high (AXL-high) state. For instance, some tumors exhibit phenotypic plasticity, dynamically switching be…

AXL/Gas6 signaling mechanisms in the hypothalamic-pituitary-gonadal axis.

AXL is a receptor tyrosine kinase commonly associated with a variety of human cancers. Along with its ligand Gas6 (growth arrest-specific protein 6), AXL is emerging as an important regulator of neuroendocrine development and function. AXL signaling in response to Gas6 binding impacts neuroendocrine structure and function at the level of the brain, pituitary, and gonads. During development, AXL has been identified as an upstream inhibitor of gonadotropin receptor hormone (GnRH) production and also plays a key role in the migration of GnRH neurons from the olfactory placode to the forebrain. AX

Taurine restores Axl/Gas6 expression in vascular smooth muscle cell calcification model.

Our previous studies demonstrated that taurine inhibits osteoblastic differentiation of vascular smooth muscular cells (VSMCs) via the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, but the underlying mechanism is not elucidated. The tyrosine kinase receptor Axl and its ligand growth arrest-specific protein 6 (Gas6) are expressed in VSMCs. Axl/Gas6 signaling system is known to inhibit VSMCs calcification. We herein showed that taurine partially restored Axl and Gas6 expression in beta-glycerophosphate (beta-GP)-induced VSMC calcification mo

AXL is an essential factor and therapeutic target for metastatic ovarian cancer.

The receptor tyrosine kinase AXL is thought to play a role in metastasis; however, the therapeutic efficacy of an AXL-targeting agent remains largely untested in metastatic disease. In this study, we defined AXL as a therapeutic target for metastatic ovarian cancer. AXL is primarily expressed in metastases and advanced-stage human ovarian tumors but not in normal ovarian epithelium. Genetic inhibition of AXL in human metastatic ovarian tumor cells is sufficient to prevent the initiation of metastatic disease in vivo. Mechanistically, inhibition of AXL signaling in animals with metastatic disea

The activated tyrosine kinase ACK1 by multiple receptor tyrosine kinases promotes proliferation and invasion of mesothelioma via regulation of PI3K/AKT/mTOR and RAF/MAPK signaling pathways.

Activation of the receptor tyrosine kinases (RTKs) EGFR, MET, and AXL has been described in subsets of mesothelioma, suggesting that tyrosine kinases (TKs) might represent therapeutic targets in this chemotherapy resistant and highly lethal cancer. In the present study, activated TKs were identified in mesothelioma cells by phosphotyrosine immunoaffinity purification and tandem mass spectrometry, and biological functions were evaluated. The results showed that non-RTK activated-CDC42 kinase 1 (ACK1) was highly expressed and activated in 8 of 9 mesothelioma cell lines and 15 of 18 mesothelioma

Axl is not an indispensable factor for Zika virus infection in mice.

Recently, Zika virus (ZIKV) outbreak has been associated with a sharp increase in cases of Guillain-Barré syndrome and severe fetal abnormalities. However, the mechanism underlying the interaction of ZIKV with host cells is not yet clear. Axl, a receptor tyrosine kinase, is postulated as a receptor for ZIKV entry; however, its in vivo role during ZIKV infection and its impact on the outcome of the disease have not been fully characterized and evaluated. Moreover, there are contradictory results on its involvement in ZIKV infection. Here we utilized Axl-deficient mice (Axl-/-) and their litterm

Downregulation of PDCD4 contributes to microglial efferocytosis and neurological function recovery following intracerebral hemorrhage.

Efferocytosis plays a vital role in mitigating inflammation and subsequent tissue damage by clearing dying cells after intracerebral hemorrh … ated microglia, Pdcd4 knockdown notably increased the expression of efferocytosis-related molecules AXL receptor tyrosine kinase (AXL) and MER proto-oncogene, tyrosine kinase (MERTK). Mechanistically, an interaction between PDCD4 and signal transducer and activator of transcription 3 (STAT3) identified under basal conditions was amplified following intracerebral hemorrhage. P …

Axl Mediates Resistance to Respiratory Syncytial Virus Infection Independent of Cell Attachment.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections in infants and young children. Axl, a TAM family receptor tyrosine kinase, has been demonstrated to be a receptor mediating enveloped virus infection. Here we show that Axl functions as a suppressor of antiviral response during RSV infection. Knockdown of Axl expression in human cells resulted in cell resistance to RSV infection, although the treatment did not significantly affect RSV binding or cell entry. Mice deficient in Axl showed resistance to RSV infection, including reduction in viral load