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      The Raine Syndrome Protein FAM20C Is a Golgi Kinase That Phosphorylates Bio-Mineralization Proteins

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          Abstract

          Raine syndrome is caused by mutations in FAM20C, which had been reported to encode a secreted component of bone and teeth. We found that FAM20C encodes a Golgi-localized protein kinase, distantly related to the Golgi-localized kinase Four-jointed. Drosophila also encode a Golgi-localized protein kinase closely related to FAM20C. We show that FAM20C can phosphorylate secreted phosphoproteins, including both Casein and members of the SIBLING protein family, which modulate biomineralization, and we find that FAM20C phosphorylates a biologically active peptide at amino acids essential for inhibition of biomineralization. We also identify autophosphorylation of FAM20C, and characterize parameters of FAM20C’s kinase activity, including its Km, pH and cation dependence, and substrate specificity. The biochemical properties of FAM20C match those of an enzymatic activity known as Golgi casein kinase. Introduction of point mutations identified in Raine syndrome patients into recombinant FAM20C impairs its normal localization and kinase activity. Our results identify FAM20C as a kinase for secreted phosphoproteins and establish a biochemical basis for Raine syndrome.

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          Most cited references35

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          Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.

          The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P(i)) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.
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            Expression analysis of G Protein-Coupled Receptors in mouse macrophages

            Background Monocytes and macrophages express an extensive repertoire of G Protein-Coupled Receptors (GPCRs) that regulate inflammation and immunity. In this study we performed a systematic micro-array analysis of GPCR expression in primary mouse macrophages to identify family members that are either enriched in macrophages compared to a panel of other cell types, or are regulated by an inflammatory stimulus, the bacterial product lipopolysaccharide (LPS). Results Several members of the P2RY family had striking expression patterns in macrophages; P2ry6 mRNA was essentially expressed in a macrophage-specific fashion, whilst P2ry1 and P2ry5 mRNA levels were strongly down-regulated by LPS. Expression of several other GPCRs was either restricted to macrophages (e.g. Gpr84) or to both macrophages and neural tissues (e.g. P2ry12, Gpr85). The GPCR repertoire expressed by bone marrow-derived macrophages and thioglycollate-elicited peritoneal macrophages had some commonality, but there were also several GPCRs preferentially expressed by either cell population. Conclusion The constitutive or regulated expression in macrophages of several GPCRs identified in this study has not previously been described. Future studies on such GPCRs and their agonists are likely to provide important insights into macrophage biology, as well as novel inflammatory pathways that could be future targets for drug discovery.
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              Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer.

              Numerous components and pathways are involved in the complex interplay between cancer cells and their environment. The family of glycophosphoproteins comprising osteopontin, bone sialoprotein, dentin matrix protein 1, dentin sialophosphoprotein and matrix extracellular phosphoglycoprotein - small integrin-binding ligand N-linked glycoproteins (SIBLINGs) - are emerging as important players in many stages of cancer progression. From their detection in various human cancers to the demonstration of their key functional roles during malignant transformation, invasion and metastasis, the SIBLINGs are proteins with potential as diagnostic and prognostic tools, as well as new therapeutic targets.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                10 August 2012
                : 7
                : 8
                : e42988
                Affiliations
                [1 ]Graduate School of Science, Chiba University, Chiba-shi, Chiba, Japan
                [2 ]Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America
                [3 ]Razavi Newman Center for Bioinformatics, Salk Institute for Biological Studies, La Jolla, California, United States of America
                National Institutes of Health (NIH), United States of America
                Author notes

                Competing Interests: The current affiliation of Dr. Xu with Simcere Pharmaceutical is not connected to the work described here, and does not constitute a conflict of interest. The current affiliation of Dr. Manning with Genentech is not connected to the work described here, and does not constitute a conflict of interest. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

                Conceived and designed the experiments: HI GM KI. Performed the experiments: HI AX EO GM. Analyzed the data: HI GM KI. Wrote the paper: HI GM KI.

                [¤a]

                Current address: Simcere Pharmaceutical, Nanjing, China.

                [¤b]

                Current address: Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, California, United States of America.

                Article
                PONE-D-12-16448
                10.1371/journal.pone.0042988
                3416761
                22900076
                2f015ca7-1ab6-447d-bf6c-cd912aa5730f
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 June 2012
                : 16 July 2012
                Page count
                Pages: 10
                Funding
                This research was supported by the Howard Hughes Medical Institute (KDI), NHGRI grant HG004164 (GM), and by Special Coordination Funds for Promoting Science and Technology and Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports and Science (HOI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Physiological Processes
                Biomineralization
                Biochemistry
                Enzymes
                Enzyme Kinetics
                Biocatalysis
                Developmental Biology
                Organism Development
                Organogenesis
                Embryology
                Genetics
                Gene Function
                Genetics of Disease
                Model Organisms
                Animal Models
                Drosophila Melanogaster
                Medicine
                Anatomy and Physiology
                Physiological Processes
                Biomineralization

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                Uncategorized

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