Phosphatidylinositol-4,5 Bisphosphate Produced by PIP5KIγ Regulates Gelsolin, Actin Assembly, and Adhesion Strength of N-Cadherin Junctions

Sayegh, Tarek Y. El; Arora, Pooja; Ling, Kun; Laschinger, Carol; Janmey, Paul A.; Anderson, Richard A.; McCulloch, Christopher A.

doi:10.1091/mbc.e06-12-1159

Cited by 64 publications

(44 citation statements)

References 55 publications

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“…A particularly novel finding was the altered expression of gelsolin in IL-1␣-and RetA-stimulated cartilage, with both treatments resulting in reduced levels of gelsolin in explant media. Gelsolin is an actincapping protein with important roles in extracellular actin scavenging (36) and regulating cytoskeletal architecture and cell-matrix interactions in many cell types, including osteoblasts, fibroblasts, and developing chondrocytes (37)(38)(39). Gelsolin is underexpressed in human RA synovial tissue (36,40), and gelsolin down-regulation is associated with cytoskeletal remodeling in arthritis synovial fibroblasts (36,41).…”

Section: Discussionmentioning

confidence: 99%

Proteomic characterization of mouse cartilage degradation in vitro

Wilson¹,

Belluoccio²,

Little³

et al. 2008

Arthritis & Rheumatism

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Objective.To develop proteomics to analyze mouse cartilage degradation and correlate transcriptional and translational responses to catabolic stimuli.Methods. Proteomic techniques were used to analyze catabolism in mouse femoral head cartilage. Using specific methods to prepare cartilage extracts and conditioned media for 2-dimensional polyacrylamide gel electrophoresis and subsequent tandem mass spectrometry, we identified novel proteins and fragments released into the media of control, interleukin-1␣ (IL-1␣)-treated, and all-trans-retinoic acid (RetA)-treated explants. Fluorescence 2-dimensional difference gel electrophoresis was used to quantify protein expression changes. We also measured changes in messenger RNA (mRNA) expression to distinguish transcriptional and posttranslational regulation of released proteins.Results. Differentially abundant proteins in the media of control and treated explants included fragments of thrombospondin 1 and connective tissue growth factor. IL-1␣ stimulated release of the cartilage degeneration marker matrix metalloproteinase 3, as well as proteins with uncharacterized roles in cartilage pathology, such as neutrophil gelatinase-associated lipocalin. RetA stimulated release of the extracellular matrix proteins cartilage oligomeric matrix protein, link protein, and matrilin-3 into the media, which was accompanied by a dramatic reduction in the corresponding mRNA transcript levels. Gelsolin, which has been implicated in cytoskeletal reorganization in arthritis synovial fibroblasts but has not been previously associated with cartilage pathology, was regulated by IL-1␣ and RetA.Conclusion. In this first analysis of mouse cartilage degradation and protein release using proteomics, we identified proteins and fragments, some of which represent novel candidate biomarkers for cartilage degradation. Applying these proteomic techniques to wild-type and genetically modified mouse cartilage will provide insights into the mechanisms of cartilage degeneration.

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Section: Discussionmentioning

confidence: 99%

Proteomic characterization of mouse cartilage degradation in vitro

Wilson¹,

Belluoccio²,

Little³

et al. 2008

Arthritis & Rheumatism

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“…In epithelial cells, PIPKIci2 regulates the formation of cell-cell contacts through its association with the adhesion molecule E-cadherin and a specific interaction with the epithelial-specific AP1B clathrin adaptor complex . Additionally, PIPKIci2 functionally links N-cadherin cell-cell junctions to regulated actin assembly (El Sayegh et al, 2007). These findings position PIPKIc as a crucial regulator of the assembly of cell-cell contacts and the intracellular transport of components of these complexes.…”

Section: Introductionmentioning

confidence: 86%

PIPKIγi5 regulates the endosomal trafficking and degradation of E-cadherin

Schill

Hedman

Choi

et al. 2014

Journal of Cell Science

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BSTRACTPhosphatidylinositol phosphate kinases (PIPKs) have distinct cellular targeting, allowing for site-specific synthesis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] to activate specific signaling cascades required for cellular processes. Several C-terminal splice variants of PIPKIc (also known as PIP5K1C) exist, and have been implicated in a multitude of cellular roles. PI(4,5)P 2 serves as a fundamental regulator of E-cadherin transport, and PI(4,5)P 2 -generating enzymes are important signaling relays in these pathways. We present evidence that the isoform 5 splice variant of PIPKIc (PIPKIci5) associates with E-cadherin and promotes its lysosomal degradation. Additionally, we show that the endosomal trafficking proteins SNX5 and SNX6 associate with PIPKIci5 and inhibit PIPKIci5-mediated Ecadherin degradation. Following HGF stimulation, activated Src directly phosphorylates PIPKIci5. Phosphorylation of the PIPKIci5 Cterminus regulates its association with SNX5 and, consequently, Ecadherin degradation. Additionally, this PIPKIci5-mediated pathway requires Rab7 to promote degradation of internalized E-cadherin. Taken together, the data indicate that PIPKIci5 and SNX5 are crucial regulators of E-cadherin sorting and degradation. PIPKIci5, SNX and phosphoinositide regulation of lysosomal sorting represent a novel area of PI(4,5)P 2 signaling and research. PIPKIci5 regulation of E-cadherin sorting for degradation might have broad implications in development and tissue maintenance, and enhanced PIPKIci5 function might have pathogenic consequences due to downregulation of E-cadherin.

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“…The clathrin adaptor complex AP-1 and, more specifically, the adaptin subunit, interacts with PIP5K to facilitate the recycling of E-cadherin . Moreover, PIP5K-mediated PtdIns(4,5)P 2 synthesis strengthens adherens junctions by competing with actin for the actinbinding protein gelsolin, resulting in an increase in actin-fibre formation (El Sayegh et al, 2007). In vivo, the deletion of PIP5K resulted in the disruption of the fascia adherens between cardiomyocytes and the disorganisation of their actin cables.…”

Section: Cell-cell Adhesionmentioning

confidence: 99%

PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions

Bout

Divecha

2009

Journal of Cell Science

277

241

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The PIP5K family Three isoforms of PIP5K have been identified and are known as PIP5K, PIP5K and PIP5K (Ishihara et al., 1996;Loijens and Anderson, 1996;Oude Weernink et al., 2004b). PIP5K and PIP5K each have a molecular mass of 64 kDa. Mouse PIP5K has three different splice variants of 69 or 72 kDa in size (Box 1). The nomenclature of PIP5K isoforms has become somewhat confusing because the nomenclature for mouse genes is opposite to that of human genes (human PIP5K is similar to mouse PIP5K and vice versa). In addition, several synonyms are currently in use for this protein family, including PI5PK, PIPK1, PI5PK1 and PIPkin. Here, we use the term PIP5K for this family together with the isoform nomenclature that is used for the human proteins, because this terminology is now used by the National Centre for Bioinformatics (NCBI) (Box 1). Further variation in the sequence of PIP5Ks is created through the generation of splice variants. In mice, eight , two  and three  splice variants have been described in the Ensemble database, whereas for humans three , four  and It has long been known that phosphoinositides are present in cellular membranes, but only in the past four decades has our understanding of their importance for proper cell function advanced significantly. Key to determining the biological roles of phosphoinositides is understanding the enzymes involved in their metabolism. Although many such enzymes have now been identified, there is still much to learn about their cellular functions. Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) are a group of kinases that catalyse the production of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P 2 ]. As well as being a substrate for the enzymes phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K), PtdIns(4,5)P 2 acts as a second messenger in its own right, influencing a variety of cellular processes. In this Commentary, we review how PIP5Ks are modulated to achieve regulated PtdIns(4,5)P 2 production, and discuss the role of these proteins in different cellular processes.

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Phosphatidylinositol-4,5 Bisphosphate Produced by PIP5KIγ Regulates Gelsolin, Actin Assembly, and Adhesion Strength of N-Cadherin Junctions

Cited by 64 publications

References 55 publications

Proteomic characterization of mouse cartilage degradation in vitro

Proteomic characterization of mouse cartilage degradation in vitro

PIPKIγi5 regulates the endosomal trafficking and degradation of E-cadherin

PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions

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