Cloning and characterization of mouse disabled 2 interacting protein 2, a mouse orthologue of human NOSTRIN

Choi, Young Joon; Cho, Si Young; Kim, Hyung Wook; Kim, Jung Ah; Bae, Seong Ho

doi:10.1016/j.bbrc.2004.11.079

Cited by 17 publications

(10 citation statements)

References 15 publications

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Section: Discussionmentioning

confidence: 99%

“…Because specifically the scaffolding peptides were shown to inhibit eNOS activity (Garcia-Cardena et al, 1997;Bucci et al, 2000), our finding suggests that NOSTRIN preferably interacts with eNOS in its inactivated state. Because the expression levels of NOSTRIN vary under (patho)physiological conditions (Choi et al, 2005;Xiang et al, 2005), it is well possible that the regulated expression of NOSTRIN may contribute to control ternary complex formation and availability.We have previously observed that the localization of NOSTRIN changes in endothelial cells dependent on the status of confluence (Zimmermann et al, 2002). Other reports showed that caveolin-1 translocates to cell-cell contacts as NIH-3T3 cells become confluent (Volonte et al, 1999) and that …”

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confidence: 99%

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Translocation of Endothelial Nitric-Oxide Synthase Involves a Ternary Complex with Caveolin-1 and NOSTRIN

Schilling

Opitz

Wiesenthal

et al. 2006

MBoC

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Recently, we characterized a novel endothelial nitric-oxide synthase (eNOS)-interacting protein, NOSTRIN (for eNOStrafficking inducer), which decreases eNOS activity upon overexpression and induces translocation of eNOS away from the plasma membrane. Here, we show that NOSTRIN directly binds to caveolin-1, a well-established inhibitor of eNOS. Because this interaction occurs between the N terminus of caveolin (positions 1-61) and the central domain of NOSTRIN (positions 323-434), it allows for independent binding of each of the two proteins to eNOS. Consistently, we were able to demonstrate the existence of a ternary complex of NOSTRIN, eNOS, and caveolin-1 in Chinese hamster ovary (CHO)-eNOS cells. In human umbilical vein endothelial cells (HUVECs), the ternary complex assembles at the plasma membrane upon confluence or thrombin stimulation. In CHO-eNOS cells, NOSTRIN-mediated translocation of eNOS involves caveolin in a process most likely representing caveolar trafficking. Accordingly, trafficking of NOSTRIN/eNOS/ caveolin is affected by altering the state of actin filaments or cholesterol levels in the plasma membrane. During caveolar trafficking, NOSTRIN functions as an adaptor to recruit mediators such as dynamin-2 essential for membrane fission. We propose that a ternary complex between NOSTRIN, caveolin-1, and eNOS mediates translocation of eNOS, with important implications for the activity and availability of eNOS in the cell. INTRODUCTIONEndothelial nitric-oxide synthase (eNOS) is the major enzyme generating nitric oxide (NO) in endothelial and epithelial cells (Ortiz and Garvin, 2003;Sessa, 2004). Because NO is an extremely reactive signaling molecule its production needs to be tightly regulated. Regulation seems to take place at three levels: direct interaction of eNOS with accessory proteins such as caveolin and Ca 2ϩ /calmodulin, reversible phosphorylation, and differential localization of the enzyme within cells. Subcellular distribution of eNOS is in part governed by lipid modification, i.e., myristoylation and dual palmitoylation, which bring about the association of the enzyme with the Golgi and plasma membrane (PM), respectively (Govers and Rabelink, 2001). Importantly, eNOS seems to be regulated by different modes in different subcellular locations, e.g., Ca 2ϩ /calmodulin stimulation is mainly effective at the PM, whereas Akt-driven activation is most pronounced at the Golgi (Fulton et al., 2004). Differential subcellular localization of eNOS is subject to dynamic regulation, e.g., after certain stimuli, the enzyme also occurs at vesicular structures throughout the cytoplasm (Nuszkowski et al., 2001;Thuringer et al., 2002). At present, however, it remains largely unknown how the differential distribution of eNOS to various subcellular locales is achieved. Emerging determinants of eNOS trafficking are eNOS-interacting proteins, which may guide eNOS to a distinct destination within the cell. In support of this model, we described two novel eNOS-interacting proteins termed NOSIP (for eNOS-inter...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Translocation of Endothelial Nitric-Oxide Synthase Involves a Ternary Complex with Caveolin-1 and NOSTRIN

Schilling

Opitz

Wiesenthal

et al. 2006

MBoC

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“…The multi-domain protein Dab2 has been proposed to function as an endocytic adaptor by linking cargo proteins, the endocytic adaptor complex-2 (AP-2) and clathrin (Mishra et al, 2002;Morris and Cooper, 2001). Thus, the reported interaction between NOSTRIN and Dab2 is well in line with a role for NOSTRIN in endocytosis, although this issue was not tackled by the authors (Choi et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was reported that the mouse ortholog of NOSTRIN interacts with Disabled-2 (Dab2) through docking of its SH3 domain to a proline-rich region of Dab2 (Choi et al, 2005). The multi-domain protein Dab2 has been proposed to function as an endocytic adaptor by linking cargo proteins, the endocytic adaptor complex-2 (AP-2) and clathrin (Mishra et al, 2002;Morris and Cooper, 2001).…”

Section: Discussionmentioning

confidence: 99%

NOSTRIN functions as a homotrimeric adaptor protein facilitating internalization of eNOS

Icking

Matt

Opitz

et al. 2005

Journal of Cell Science

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Intracellular trafficking of endothelial nitric oxide synthase (eNOS) between different compartments is incompletely understood. Recently, we described a novel eNOS-interacting protein, NOSTRIN, which upon overexpression drives eNOS away from the plasma membrane towards intracellular compartments. Sequence similarity of NOSTRIN and pacsins/syndapins suggested a role for NOSTRIN in endocytosis. Accordingly, we show here that NOSTRIN interacts with the large GTPase dynamin and the actin nucleation promoting factor N-WASP by means of its SH3 domain, which also represents the docking site for eNOS. Via a coiled-coil region in the C-terminal portion of the protein, NOSTRIN oligomerizes, mainly forming trimers, which would allow simultaneous interaction with multiple binding partners of the SH3 domain. Consistent with this notion, expression of dynamin-2-GFP in CHO cells stably expressing eNOS (CHO-eNOS) results in recruitment of eNOS to dynamin-positive structures, only when NOSTRIN is present as well. Similarly, when N-WASP-GFP and NOSTRIN are co-expressed in CHO-eNOS cells, both proteins strongly co-localize with eNOS and are recruited to structures running along actin filaments. If, however, the actin cytoskeleton is depolymerized by cytochalasin D, NOSTRIN and eNOS are associated with extended structures in the cell periphery, possibly being unable to leave the plasma membrane. Together, these results indicate that NOSTRIN may facilitate endocytosis of eNOS by coordinating the function of dynamin and N-WASP.

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“…Whether the decreased expression of the genes Nostrin (LOC329416), Bmper and Pthr1 is a direct effect of deficient FGFR signalling remains to be elucidated. However, they have been linked to developmental processes during embryogenesis (Choi et al, 2005;Moser et al, 2003;MacLean and Kronenberg, 2005). Also, the expression of Clic6 and Tcfec was down-regulated at day 1 of 1c6 EB development.…”

Section: Influence Of the Fgfr2 Mutation On Gene Expression Studied Bmentioning

confidence: 99%

Gene expression profiling of differentiating embryonic stem cells expressing dominant negative fibroblast growth factor receptor 2

et al. 2007

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Embryonic stem (ES) cells are derived from the inner cell mass of the blastocyst and can be cultured as three-dimensional embryoid bodies (EBs) in which embryonic pregastrulation stages are faithfully mimicked. Fibroblast growth factor receptors (mainly FGFR2) are involved in the first differentiation events during early mammalian embryogenesis. It has been demonstrated that the presence of FGFR2 is a prerequisite for laminin-111 and collagen type IV synthesis and subsequently basement membrane formation in EBs. To identify genes that are influenced by FGFR signalling, we performed global gene expression profiling of differentiating EBs expressing dominant negative FGFR2 (dnFGFR2), acquiring an extensive catalogue of down-and up-regulated genes. We show a strong down-regulation of endodermal and basement membrane related genes, which strengthen the view that the FGFR signalling pathway is a main stimulator of basement membrane synthesis in EBs. We further present down-regulation of genes previously not linked to FGFR signalling, and in addition an active transcription of some mesodermal related genes in differentiating dnFGFR2 EBs.

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Cloning and characterization of mouse disabled 2 interacting protein 2, a mouse orthologue of human NOSTRIN

Cited by 17 publications

References 15 publications

Translocation of Endothelial Nitric-Oxide Synthase Involves a Ternary Complex with Caveolin-1 and NOSTRIN

Translocation of Endothelial Nitric-Oxide Synthase Involves a Ternary Complex with Caveolin-1 and NOSTRIN

NOSTRIN functions as a homotrimeric adaptor protein facilitating internalization of eNOS

Gene expression profiling of differentiating embryonic stem cells expressing dominant negative fibroblast growth factor receptor 2

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