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In vitro phosphorylation of trypsin-digested K562 cell lysate by TAM family kinases

ABSTRACT: K562 cell lysate was digested with trypsin, dephosphorylated with lambda phosphatase, and treated in an in vitro kinase reaction with Axl, Mer or Tyro3 kinase, alongside a control reaction for each that contained no kinase. Samples were phosphoenriched with the SMOAC approach (TiO2 and FeNTA) and analyzed on an Orbitrap-Velos. Peptides were identified using PEAKS Studio X Pro.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Laurie Parker

PROVIDER: MSV000092784 | MassIVE | Tue Aug 29 16:34:00 BST 2023

SECONDARY ACCESSION(S): PXD044943

REPOSITORIES: MassIVE

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Publications

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

Widstrom Naomi E NE Andrianov Grigorii V GV Heier Jason L JL Heier Celina C Karanicolas John J Parker Laurie L LL

ACS chemical biology 20231230 1

The TAM family of receptor tyrosine kinases is implicated in multiple distinct oncogenic signaling pathways. However, to date, there are no FDA-approved small molecule inhibitors for the TAM kinases. Inhibitor design and screening rely on tools to study the kinase activity. Our goal was to address this gap by designing a set of synthetic peptide substrates for each of the TAM family members: Tyro3, Axl, and Mer. We used an in vitro phosphoproteomics workflow to determine the substrate profile of ...[more]

PMID: 38159292

Similar Datasets

The TAM receptor tyrosine kinases Axl and Mer drive the phagocytic differentiation of tissue-resident macrophages

Project description:Many apoptotic thymocytes are generated during the course of T cell selection in the thymus, yet the machinery through which these dead cells are recognized and phagocytically cleared is incompletely understood. We find that the TAM receptor tyrosine kinases Axl and Mer, which are co-expressed by a specialized set of phagocytic thymic macrophages, are essential components of this machinery. Axl-/-Mertk-/- double mutant mice exhibited a marked accumulation of apoptotic cells during the time that autoreactive and nonreactive thymocytes die. Unexpectedly, the double mutants also displayed a profound deficit in the total number of phagocytic macrophages in the thymus, and concomitantly exhibited diminished expression of key non-TAM engulfment systems in the macrophages that remain. These previously unrecognized deficits were not confined to the thymus, and were also evident in the bone marrow and spleen. They had pleiotropic metabolic consequences for the double mutants, which included severe dysregulation of hemoglobin turnover, iron metabolism, and erythropoiesis.

2022-07-12 | GSE192363 | GEO

Identification of AXL interactome by proximity-dependent protein identification (BioID)

Project description:AXL is a receptor tyrosine kinase (RTK) which, together with TYRO3 and MER, belongs to the TAM receptor family. A ligand for AXL is growth arrest specific 6 (GAS6), which is able to bind all three TAMs with the highest affinity for AXL. AXL is overexpressed in a variety of different cancers, which correlates with poor prognosis, metastasis and drug resistance. However, its biology is still not fully understood and data concerning proteins that interact with this receptor are almost completely lacking. To identify mechanisms underlying the role of GAS6-AXL signaling in cancer, we established an AXL interactome using proximity-dependent biotin identification (BioID) assay. Experiments were conducted in HEK293 cells and human glioblastoma LN229 cells, which do not express and express AXL, respectively. The Gene Ontology (GO) analysis of biological processes indicated enrichment of proteins implicated in cell junction organization, axonogenesis, supramolecular fiber organization, angiogenesis and actin-related processes in bot, non-stimulated and GAS6-stimulated samples. Importantly, in samples with activated AXL, proteins implicated in actin-related processes were overrepresented. Consistent with this, we found that GAS6 stimulation triggered actin remodeling manifested by intense membrane ruffling and macropinocytosis. Our study provides comprehensive data about proteins interacting with AXL. Thus, the obtained results will help to understand the biology of the AXL receptor, particularly with respect to its involvement in cancer invasion.

2021-06-28 | PXD017933 | Pride

Microglia use TAM receptors to detect and engulf amyloid beta plaques

Project description:Two microglial TAM receptor tyrosine kinases - Axl and Mer - have been linked to Alzheimer’s disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer’s disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia is coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer’s disease, sIngle cell RNAseq analysis comparing wild type microglia with those with Axl and Mer deficiency reveals a similar disease state transitional program of microglia but a dampened differential expression of numerous AD siganture genes in microglia lacking TAM receptors. In line with the transcriptomic data, using two-photon microscopy, we show that genetic ablation of Axl and Mer results in microglia that are unable to normally detect, respond to, organize, or phagocytose amyloid beta plaques. These major deficits notwithstanding, and contrary to expectation, TAM-deficient APP/PS1 mice develop fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques, and that TAM-driven microglial phagocytosis does not constrain, but rather promotes, plaque development.

2021-02-25 | GSE160523 | GEO

The TAM receptor tyrosine kinases Axl and Mer drive the phagocytic differentiation of tissue-resident macrophages

Project description:The TAM receptor tyrosine kinases Axl and Mer drive the phagocytic differentiation of tissue-resident macrophages

| PRJNA791287 | ENA

Reduced Proteolytic Shedding of Receptor Tyrosine Kinases is a Post-Translational Mechanism of Kinase Inhibitor Resistance.

Project description:Expression data from MDA-MB231 human breast cancer cells treated with metalloproteinase inhibitor (10uM BB94), MEK inhibitor (3uM PD325901), or DMSO control shows substantial overlap in the transcriptional responses arising from MEK and protease inhibition, suggesting a shared mechanism of action. Kinase inhibitor resistance often involves upregulation of poorly understood “bypass” signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTKs) including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of melanoma patients treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured non-invasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.

2016-03-21 | GSE77868 | GEO

Expression data from knockdown of Tyro3 in hepatocellular carcinoma

Project description:Tyro3 is a member of the TAM (Tyro3, Axl and Mer) receptor family. In this study, we want to know potential association between Tyro3 expression in HCC and the involved signaling pathway.

2018-09-04 | GSE119388 | GEO

Identification of the receptor tyrosine kinase AXL in triple negative breast cancer as a novel target for the human miR-34a microRNA

Project description:This SuperSeries is composed of the following subset Series: GSE21719: Identification of the receptor tyrosine kinase AXL in triple negative breast cancer as a novel target for the human miR-34a microRNA (miRNA study) GSE21832: Identification of the receptor tyrosine kinase AXL in triple negative breast cancer as a novel target for the human miR-34a microRNA (gene expression) Refer to individual Series

2010-12-31 | E-GEOD-21834 | biostudies-arrayexpress

Effect of Gas6/Axl on HCC cell line gene expression

Project description:We adressed the impact of the receptor tyrosine kinase Axl and ist ligand Gas6 on gene expression in cellular HCC models, including cells harbouring Axl KO and exogenous reexpression.

2023-04-20 | GSE229731 | GEO

AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.

Project description:Phosphoinositide-3-kinase (PI3K)-α inhibitors are clinically active in squamous carcinoma (SCC) of the head and neck (H&N) bearing mutations or amplification of PIK3CA. We aimed to identify potential mechanism of resistance and have observed that SCCs cells overcome the antitumor effects of the PI3Kα inhibitor BYL719 by maintaining PI3K-independent activation of the mammalian target of rapamycin (mTOR). The persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. We found that AXL is overexpressed in resistant tumors, dimerizes with the epidermal growth factor receptor (EGFR), phosphorylates EGFR tyrosine 1173, resulting in activation of phospholipase Cγ (PLCγ)- protein kinase C (PKC) that, in turn, activates mTOR. Finally, simultaneous treatment with PI3Kα and either EGFR, AXL or PKC inhibitors reverts this resistance. RNAseq from acquired resistant cells CAL33B, K180B were compared to their parental counterpart CAL33 and K180, respectively. K180 is a shortcut of KYSE180, and B stands for BYL719. Duplicate of parental sensitive cells and K180B, and triplicate for CAL33B.

2015-04-12 | E-GEOD-61515 | biostudies-arrayexpress

Gene expression analysis of dissociated and FDG FACS-sorted mammary glands of 16 week old nulliparous AXL +/LacZ and AXL LacZ/LacZ mice (B6.129P2-AXLtm1Dgen strain, Jackson Labs)

Project description:The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony-formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl+ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers, and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when coopted, maintains acquired stemness in breast cancer cells.

2020-08-25 | GSE156662 | GEO

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