Identification of the Wnt signaling activator leucine-rich repeat in Flightless interaction protein 2 by a genome-wide functional analysis

Li, Jun; Bang, Anne G.; Kintner, Chris; Orth, Anthony P.; Chanda, Sumit K.; Ding, Sheng; Schultz, Peter G.

doi:10.1073/pnas.0409472102

Cited by 73 publications

(67 citation statements)

References 38 publications

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“…Phosphorylation of Lrrfip1 at Ser-88 and Lrrfip2 at Ser-133, both part of putative PKA consensus sites, were increased by vasopressin. Lrrfip isoforms positively regulate ␤-catenin-dependent gene transcription (67)(68)(69). These data are consistent with the hypothesis that vasopressin may act as a potentiator of Wnt pathway signaling.…”

Section: Phosphoproteomics Of G Protein-coupled Receptor Signalingsupporting

confidence: 88%

Dynamics of the G Protein-coupled Vasopressin V2 Receptor Signaling Network Revealed by Quantitative Phosphoproteomics

Hoffert

Pisitkun

Saeed

et al. 2012

Molecular & Cellular Proteomics

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G protein-coupled receptors (GPCRs) regulate diverse physiological processes, and many human diseases are due to defects in GPCR signaling. To identify the dynamic response of a signaling network downstream from a prototypical G s -coupled GPCR, the vasopressin V2 receptor, we have carried out multireplicate, quantitative phosphoproteomics with iTRAQ labeling at four time points following vasopressin exposure at a physiological concentration in cells isolated from rat kidney. A total of 12,167 phosphopeptides were identified from 2,783 proteins, with 273 changing significantly in abundance with vasopressin. Two-dimensional clustering of phosphopeptide time courses and Gene Ontology terms revealed that ligand binding to the V2 receptor affects more than simply the canonical cyclic adenosine monophosphateprotein kinase A and arrestin pathways under physiological conditions. The regulated proteins included key components of actin cytoskeleton remodeling, cell-cell adhesion, mitogen-activated protein kinase signaling, Wnt/␤-catenin signaling, and apoptosis pathways. These data suggest that vasopressin can regulate an array of cellular functions well beyond its classical role in regulating water and solute transport. These results greatly expand the current view of GPCR signaling in a physiological context and shed new light on

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Section: Phosphoproteomics Of G Protein-coupled Receptor Signalingsupporting

confidence: 88%

Dynamics of the G Protein-coupled Vasopressin V2 Receptor Signaling Network Revealed by Quantitative Phosphoproteomics

Hoffert

Pisitkun

Saeed

et al. 2012

Molecular & Cellular Proteomics

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“…3B). Our findings are consistent with reports that the overexpression of CK1-␦ or -are sufficient to activate the WNT signaling, but CK1-␣, CK1-␥, and CK2-␣ could not induce any significant activation of ␤-catenin reporter (36)(37)(38).…”

Section: Expression Of Kinases In Mammalian Cellssupporting

confidence: 93%

“…The kinase clones described here add to the growing number of recently generated human ORF and arrayed cDNA clone collections, which allow indexed experimentation at the gene family or subgenome scales (38,44,45). Future challenges on this area are the completion of relevant gene-family ORF collections (13)(14)(15) (to include all genes in a given gene family and all alternative spliced forms of every gene) and the production of clone isolates with full-length sequence verification (such as the clones in this study) for all predicted human ORFs.…”

Section: Bacterial Expression and Purification For Autophosphorylatiomentioning

confidence: 99%

Building a human kinase gene repository: Bioinformatics, molecular cloning, and functional validation

Park

Murthy

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides, and other important cellular metabolites and play key regulatory roles in all aspects of eukaryotic cell physiology. Here, we describe the mining of public databases to collect the sequence information of all identified human kinase genes and the cloning of the corresponding ORFs. We identified 663 genes, 511 encoding protein kinases, and 152 encoding nonprotein kinases. We describe the successful cloning and sequence verification of 270 of these genes. Subcloning of this gene set in mammalian expression vectors and their use in high-throughput cell-based screens allowed the validation of the clones at the level of expression and the identification of previously uncharacterized modulators of the survivin promoter. Moreover, expressions of the kinase genes in bacteria, followed by autophosphorylation assays, identified 21 protein kinases that showed autocatalytic activity. The work described here will facilitate the functional assaying of this important gene family in phenotypic screens and their use in biochemical and structural studies.kinome ͉ autophosphorylation ͉ cell-based screens ͉ high-throughput cloning ͉ survivin T he term kinase refers to a large number of mechanistically, structurally, and evolutionary distinct classes of enzymes. They catalyze the transfer of the ␥-phosphate from nucleoside triphosphates to a large number of molecules, including proteins, sugars, nucleosides, and lipids, and affect the activity and fate of those molecules and the cell.Phosphorylation is a common posttranslational modification of proteins and plays a key role on protein structure and function and in all aspects of cell physiology. Protein kinases contain well conserved motifs and constitute the largest family of proteins in the human genome (1-3). Mutations of protein kinases are involved in carcinogenesis and several other pathological conditions (4-6). Phosphorylations of other biomolecules also play a critical role in the physiology and pathology of cells. Lipid kinases such as the phosphoinositide-3 kinase family members are key modulators of the cellular response to growth factors, hormones, and neurotransmitters and are involved in cancer (7). Nucleotide and nucleoside kinases regulate the intracellular levels of phosphate donors and nucleic acid precursors and are involved in the cellular response to damage and ischemia (8, 9). Sugar kinases regulate the rates of sugar metabolism, energy generation, and transcription activation and are involved in the process of cellular transformation and apoptosis (10-12).The near completion of the Human Genome Project, the ongoing annotation projects, and the availability of sequence databases has allowed the genome-scale search and identification of members of different gene families by using sequence information as well as structural or functional annotations (2, 3, 13-15). However, a systematic cloning, sequence analysis, and functional validation effort for any of these gene sets has been chal...

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“…3B). LRRFIP2 encodes a protein that activates Wnt signaling (38). LRRFIP2 was identified here as a candidate gene for alternative splicing in colon and prostate cancer (Table II).…”

Section: Figmentioning

confidence: 99%

Alternative Splicing in Colon, Bladder, and Prostate Cancer Identified by Exon Array Analysis

Thorsen¹,

Sørensen²,

Brems-Eskildsen³

et al. 2008

Molecular & Cellular Proteomics

216

222

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Alternative splicing enhances proteome diversity and modulates cancer-associated proteins. To identify tissueand tumor-specific alternative splicing, we used the GeneChip Human Exon 1.0 ST Array to measure wholegenome exon expression in 102 normal and cancer tissue samples of different stages from colon, urinary bladder, and prostate. We identified 2069 candidate alternative splicing events between normal tissue samples from colon, bladder, and prostate and selected 15 splicing events for RT-PCR validation, 10 of which were successfully validated by RT-PCR and sequencing. Furthermore 23, 19, and 18 candidate tumor-specific splicing alterations in colon, bladder, and prostate, respectively, were selected for RT-PCR validation on an independent set of 81 normal and tumor tissue samples. In total, seven genes with tumor-specific splice variants were identified (ACTN1, CALD1, COL6A3, LRRFIP2, PIK4CB, TPM1, and VCL). The validated tumor-specific splicing alterations were highly consistent, enabling clear separation of normal and cancer samples and in some cases even of different tumor stages. A subset of the tumor-specific splicing alterations (ACTN1, CALD1, and VCL) was found in all three organs and may represent general cancer-related splicing events. In silico protein predictions suggest that the identified cancerspecific splice variants encode proteins with potentially altered functions, indicating that they may be involved in pathogenesis and hence represent novel therapeutic targets. In conclusion, we identified and validated alternative splicing between normal tissue samples from colon, bladder, and prostate in addition to cancerspecific splicing events in colon, bladder, and prostate Alternative splicing is a key component in expanding a relatively limited number of genes into very complex proteomes. It has been estimated that about three-quarters of all human genes undergo alternative splicing (1-3), which may affect function, localization, binding properties, and stability of the encoded proteins (4). The recent results from the ENCODE (Encyclopedia of DNA Elements) consortium (5) extend and confirm the ubiquity of alternative splicing (6). Several splice variants with antagonistic functions have been described, e.g. BCL-X has an antiapoptotic long isoform and a proapoptotic short isoform (7,8). Alternative splicing can also lead to degradation of the transcript, thereby abrogating protein expression; examples include certain Serine/Arginine-rich (SR) protein splicing factors for which the inclusion of a particular exon causes mRNA degradation by nonsense-mediated decay (9, 10).Single nucleotide polymorphisms and somatic splice site mutations leading to aberrant splicing patterns have been described for a number of tumor suppressor genes, including APC, TP53, and BRCA1 (11). Deregulation of trans-acting proteins, such as splicing factors and heterogeneous nuclear ribonucleoproteins, may cause a more general change in RNA splicing in cancer cells. The SFRS1 gene, encoding the splicing factor 2/alternate spli...

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Identification of the Wnt signaling activator leucine-rich repeat in Flightless interaction protein 2 by a genome-wide functional analysis

Cited by 73 publications

References 38 publications

Dynamics of the G Protein-coupled Vasopressin V2 Receptor Signaling Network Revealed by Quantitative Phosphoproteomics

Dynamics of the G Protein-coupled Vasopressin V2 Receptor Signaling Network Revealed by Quantitative Phosphoproteomics

Building a human kinase gene repository: Bioinformatics, molecular cloning, and functional validation

Alternative Splicing in Colon, Bladder, and Prostate Cancer Identified by Exon Array Analysis

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