Cell Cycle-Regulated Inactivation of Endothelial NO Synthase through NOSIP-Dependent Targeting to the Cytoskeleton

Schleicher, Michael; Brundin, Fredrik; Gross, Steffen; Müller‐Esterl, Werner; Oess, Stefanie

doi:10.1128/mcb.25.18.8251-8258.2005

Cited by 38 publications

(71 citation statements)

References 42 publications

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“…50,51 In platelets, Hsp90 has been shown to associate with NOS3 and to enhance its activity in response to insulin 31 and after binding to the globular form of ␤-actin. 26 In endothelial cells, NOSIP and NOSTRIN both inhibit, 52,53 and dynamin-2 and porin both augment, 54,55 NOS3 activity. However, at present nothing is known about the possible regulation of NOS3 in platelets by these proteins.…”

Section: The L-arginine-no Pathway In Plateletsmentioning

confidence: 99%

Platelet-Derived Nitric Oxide Signaling and Regulation

Gkaliagkousi

Ritter

Ferro

2007

Circulation Research

145

103

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Abstract-Nitric oxide (NO) exerts important vasodilatory, antiplatelet, antioxidant, antiadhesive, and antiproliferative effects. Although endothelium derived NO has been shown to be of prime importance in cardio-and vasculoprotection, until recently little was known about the role of platelet-derived NO. New evidence suggests that NO synthesized by platelets regulates platelet functions, in particular suppressing platelet activation and intravascular thrombosis. Moreover, platelet NO biosynthesis may be decreased in patients with cardiovascular risk factors or with coronary heart disease, and this may contribute to arterial thrombotic disease in these patients. Here, we review the current state of knowledge as regards the role of platelet-derived NO, both in normal physiology and in cardiovascular disease states, and compare platelet NO signaling and regulation with that in endothelial cells. (Circ Res. 2007;101:654-662.)

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Section: The L-arginine-no Pathway In Plateletsmentioning

confidence: 99%

Platelet-Derived Nitric Oxide Signaling and Regulation

Gkaliagkousi

Ritter

Ferro

2007

Circulation Research

145

103

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“…Recently, we described two novel eNOSinteracting proteins termed NOSIP (eNOS interacting protein) and NOSTRIN (eNOS trafficking inducer), both of which influence localization of eNOS. For NOSIP, targeting of eNOS to the cytoskeleton appears to be one of the protein's major functions (Schleicher et al, 2005). Interaction of eNOS with NOSTRIN, by contrast, leads to translocation of eNOS from the plasma membrane to intracellular vesicular structures, most likely through an endocytic process (Zimmermann et al, 2002).…”

Section: Introductionmentioning

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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“…In support of this model, we described two novel eNOS-interacting proteins termed NOSIP (for eNOS-interacting protein) and NOSTRIN (for eNOS-trafficking inducer), which both influence localization of eNOS. For NOSIP, targeting of eNOS to the cytoskeleton seems to be one of the protein's major functions (Schleicher et al, 2005). Overexpression of NOSTRIN, in contrast, leads to translocation of eNOS from the PM to intracellular vesicular structures (Zimmermann et al, 2002), possibly involving an endocytic process (Icking et al, 2005).…”

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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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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Cell Cycle-Regulated Inactivation of Endothelial NO Synthase through NOSIP-Dependent Targeting to the Cytoskeleton

Cited by 38 publications

References 42 publications

Platelet-Derived Nitric Oxide Signaling and Regulation

Platelet-Derived Nitric Oxide Signaling and Regulation

NOSTRIN functions as a homotrimeric adaptor protein facilitating internalization of eNOS

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

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