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Determination of PIK3C2B binding small GTPases

ABSTRACT: Identify small GTPases of the Rab family of small GTPases that regulate PIK3C2B

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Alexander Wallroth

LAB HEAD: Volker Haucke

PROVIDER: PXD014530 | Pride | 2019-10-02

REPOSITORIES: pride

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			Action	DRS
	2_PeptideSummaryReport.htm	Other
	E_20170905_HS780_2.raw	Raw

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Publications

Protein kinase N controls a lysosomal lipid switch to facilitate nutrient signalling via mTORC1.

Wallroth Alexander A Koch Philipp A PA Marat Andrea L AL Krause Eberhard E Haucke Volker V

Nature cell biology 20190826 9

Mechanistic target of rapamycin (mTOR) kinase functions in two multiprotein complexes: lysosomal mTOR complex 1 (mTORC1) and mTORC2 at the plasma membrane. mTORC1 modulates the cell response to growth factors and nutrients by increasing protein synthesis and cell growth, and repressing the autophagy-lysosomal pathway1-4; however, dysfunction in mTORC1 is implicated in various diseases3,5,6. mTORC1 activity is regulated by phosphoinositide lipids7-10. Class I phos ...[more]

PMID: 31451768

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Phosphoproteome Profiling of the Receptor Tyrosine Kinase MuSK Identifies Tyrosine Phosphorylation of Rab GTPases.

Project description:Muscle-specific receptor tyrosine kinase (MuSK) agonist antibodies were developed two decades ago to explore the benefits of receptor activation at the neuromuscular junction. Unlike agrin, the endogenous agonist of MuSK, MuSK agonist antibodies function independently of its co-receptor Lrp4. Recent reports suggest that MuSK agonist antibodies can delay the onset of muscle denervation in mouse models of amyotrophic lateral sclerosis (ALS). To get a deeper understanding of MuSK signaling, and potentially identify Lrp4-independent signaling downstream of MuSK activation, we performed phosphoproteome profiling of myotubes treated with each agonist. Our approach involved quantifying changes in site-specific phosphorylation in orthogonal dose response and time course experiments with each agonist using isobaric mass tags. We observed that both agonists elicited remarkably similar intracellular responses, as evidenced by highly correlating tyrosine phosphorylation on known MuSK signaling components and newly identified cytoskeletal and intracellular trafficking nodes. Among these was inducible phosphorylation on a conserved N-terminal phosphorylation site present on a family of endosomal Rab GTPases. We confirmed that suppression of MuSK signaling by a small molecule reduces Rab10 tyrosine phosphorylation. Importantly, Rab10 mutation at this site disrupts its association with adaptor molecules Mical1 and Mical3. Together these data provide an in depth characterization of the MuSK signaling pathway, describe two small molecule kinase inhibitors, and reveal a novel regulatory mechanism of small Rab GTPases that is poised to regulate intracellular trafficking downstream of receptor tyrosine kinase activation.

2020-06-04 | MSV000085547 | MassIVE

Transcriptional profiling of the cellular transformation induced by Rho subfamily GTPases

Project description:We have used microarray technology to identify the transcriptional targets of Rho subfamily GTPases. This analysis indicated that murine fibroblasts transformed by these proteins show similar transcriptomal profiles. Functional annotation of the regulated genes indicate that Rho subfamily GTPases target a wide spectrum of biological functions, although loci encoding proteins linked to proliferation and DNA synthesis/transcription are up-regulated preferentially. Rho proteins promote four main networks of interacting proteins nucleated around E2F, c-Jun, c-Myc, and p53. Of those, E2F, c-Jun and c-Myc are essential for the maintenance of cell transformation. Inhibition of Rock, one of the main Rho GTPase targets, leads to small changes in the transcriptome of Rho-transformed cells. Rock inhibition decreases c-myc gene expression without affecting the E2F and c-Jun pathways. Loss-of-function studies demonstrate that c-Myc is important for the blockage of cell-contact inhibition rather than for promoting the proliferation of Rho-transformed cells. However, c-Myc overexpression does not bypass the inhibition of cell transformation induced by Rock blockage, indicating that c-Myc is essential, but not sufficient, for Rock-dependent transformation. These results reveal the complexity of the genetic program orchestrated by the Rho subfamily and pinpoint protein networks that mediate different aspects of the malignant phenotype of Rho-transformed cells Keywords: Rho/Rac GTPases, microarray, oncogenesis, proliferation, gene expression, transcription, Rock, c-Myc

2007-01-03 | GSE5913 | GEO

Effect of Rinl deficiency on ex vivo isolated naïve and effector/memory CD4+ T cells

Project description:Rab GTPases are primarly involved in trafficking processes. Rinl belongs to the Ras-interaction/interference (Rin) proteins and is a guanine nucleotide exchange factor (GEF) for Rab5a and Rab22. By transcriptome analysis of naïve and effector CD4+ T cells we identify Rinl-regulated pathways in CD4+ T cells.

2023-08-28 | GSE235805 | GEO

Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases

Project description:Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson’s disease (PD). G2019S, the most common amino acid substitution activates the kinase two to three-fold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD.

2016-02-04 | PXD003071 | Pride

Comparative proteomic identification of Rab GTPase interactors in Arabidopsis

Project description:Rab GTPases are key spatio-temporal regulators of endomembrane trafficking and endomembrane compartment identity across eukaryotes. This therefore makes them ideal targets for study of endomembrane compartment and trafficking pathway composition. In plants, few definitive interactors of Rab GTPases and cargoes of their associated trafficking pathways are known, hindering our understanding of how plants may accomplish and support some unique aspects and requirements of their post-Golgi trafficking systems. The purpose of this work was to identify candidate interactors of different post-Golgi Rab GTPases in Arabidopsis. Co-IPs were performed against tagged-versions of three different post-Golgi Rab GTPases: RAB-A5c, RAB-A2a and RAB-G3f, as well as against control wild-type (Col-0) plants. Comparative ranking of the different proteomes produced candidate interactor lists enriched in possible specific interactors of each Rab GTPase, as well as generic shared interactors. This dataset forms the basis of the characterisation work of several upcoming publications.

2023-09-21 | PXD044263 | Pride

Structural basis for the specificity of PPM1H phosphatase for Rab GTPases

Project description:LRRK2 serine/threonine kinase is associated with inherited Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases within their switch 2 motif to control their interactions with effectors. Recent work has shown that the metal-dependent protein phosphatase PPM1H counteracts LRRK2 by dephosphorylating Rabs. PPM1H is highly selective and closely related PPM1J/M exhibit virtually no activity toward substrates such as Rab8a phosphorylated at T72 (pT72). Here we have identified the structural determinant of PPM1H specificity for Rabs. The crystal structure of PPM1H reveals a conserved catalytic domain that adopts a β-sandwich fold. The striking difference is that PPM1H has evolved a 110-residue flap domain that punctuates the catalytic domain. The flap domain distantly resembles tudor domains that interact with histones in the context of epigenetics. Cellular assays and 3-D modelling suggest that the flap domain encodes the docking motif for phosphorylated Rabs. Consistent with this hypothesis, a PPM1J chimera with the PPM1H flap domain dephosphorylates pT72 of Rab8a with a higher specific activity than PPM1H. Therefore, PPM1H has acquired a Rab-specific interaction domain within a conserved phosphatase fold.

2021-08-11 | PXD026367 | Pride

Rab30 regulates lipid homeostasis in the hepatocyte during fasting

Project description:In order to facilitate inter-tissue communication and exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Rab30, a putative Golgi-localized Rab GTPase, is induced in the mouse liver by fasting and its expression is further amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2L-/-) that lack the ability to oxidize fatty acids in a Pparα-dependent manner. Live-cell super-resolution imaging and biochemical in vivo proximity labeling demonstrated that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30;Cpt2 liver-specific double knockout (DKO) mice are viable and display intact Golgi ultrastructure. However, the loss of Rab30 in Rab30;Cpt2 DKO mice suppresses serum dyslipidemia observed in Cpt2L-/- single knockout mice. Corresponding with decreased serum triglyceride and cholesterol levels, Rab30;Cpt2 DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels particularly during times of excessive lipid burden.

2024-05-04 | PXD050376 | Pride

HDX-MS of TRAPPII reveals a conserved Rab binding interface

Project description:We used hydrogen deuterium exchange mass spectrometry (HDX-MS) to define the interface of TRAPPII with three Rab GTPases (Rab1, Rab11, Rab43). These experiments were performed in the presence of EDTA to generate a nucleotide free stabilised Rab-GEF complex. Significant decreases in deuterium incorporation (defined as >4%, >0.4Da, two tailed T-test p value <0.01) were identified in the TRAPPC2L, TRAPPC4, and TRAPPC5 in the presence of Rab GTPases with no other changes in other TRAPP subunits. Here we show that all three Rab GTPases bind at a conserved interface of TRAPPII.

2020-12-11 | PXD020890 | Pride

Targeted proteomic analysis of small GTPases in radioresistant breast cancer cells

Project description:Radiotherapy benefits more than 50% of cancer patients and cures 40% of them, where ionizing radiation deposits energy to cells and tissues, thereby eliciting DNA damage and resulting in cell death. Small GTPases are a superfamily of proteins that play critical roles in cell signaling. Several small GTPases, including RAC1, RHOB and RALA, were previously shown to modulate radioresistance in cancer cells. However, there is no systematic proteomic study on small GTPases that regulate radioresistance in cancer cells. Herein, we applied a high-throughput scheduled multiple-reaction monitoring (MRM) method, along with the use of synthetic stable isotope-labeled peptides, to identify differentially expressed small GTPase proteins in two pairs of breast cancer cell lines, MDA-MB-231 and MCF7, and their corresponding radioresistant lines. We identified 7 commonly altered small GTPase proteins with over 1.5-fold change in the two pairs of cell lines. We also discovered ARFRP1 as a novel radioresistance regulator, where its downregulation promotes radioresistance in breast cancer cells. Together, this represents the first comprehensive assessment about the differential expression of the small GTPase proteome associated with the development of radioresistance in breast cancer cells. Our work also uncovered ARFRP1 as a new target for enhancing radiation sensitivity in breast cancer.

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