The flotillins are integral membrane proteins in lipid rafts that contain TCR-associated signaling components: implications for T-cell activation

Slaughter, Ndaisha; Laux, Isett; Tu, Xiaolin; Whitelegge, Julian P.; Zhu, Xiaoming; Effros, Rita B.; Bickel, Perry E.; Nel, André E.

doi:10.1016/s1521-6616(03)00097-4

Cited by 79 publications

(177 citation statements)

References 61 publications

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“…In 3T3 fibroblasts, reggie-2 is predominantly found on intracellular granules but relocates to the plasma membrane upon differentiation to adipocytes [41]. Similarly, in RAW 264.7 macrophages (which despite a contrary report [42] express both reggies), reggie-2 is almost exclusively found on intracellular vesicular organelles while reggie-1 is found predominantly at the plasma membrane [our own unpublished observations]. In phagocytic cells reggie-2 was also observed on phagosomes [43], where it accumulates during maturation of the phagosome by fusion with endosomes [44].…”

Section: Subcellular Localization and Trafficking Of Reggiesmentioning

confidence: 95%

“…This suggests involvement of reggies in signal transduction by GPI-anchored proteins across the plasma membrane. Accordingly, reggies seem to be quite closely associated with the Src-family kinases lck and fyn [29,41,42], as shown by both co-immunoprecipitation and co-localization at the light microscopic (LM) and electron microscopic (EM) level. Several large transmembrane proteins have also been co-immunoprecipitated with reggies, including ABCA1 [55], an ABC transporter implicated in cholesterol transport to highdensity lipoprotein particles.…”

Section: Cellular Function Of Reggie Proteinsmentioning

confidence: 96%

“…Both reggies are expressed in B and T lymphocytes [17,29]. In T cells, reggie-1 and -2 are associated with the Src-kinases lck and fyn as shown by co-immunoprecipitation [29,31,42,62]. Reggie-2 binds fyn regardless of its activity, as it also binds to the kinase-dead mutant [41].…”

Section: Cellular Function Of Reggie Proteinsmentioning

confidence: 99%

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Scaffolding microdomains and beyond: the function of reggie/flotillin proteins

Langhorst

Reuter

Stuermer

2005

Cell. Mol. Life Sci.

288

273

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Abstract. Reggie/flotillin proteins are considered to be components of lipid rafts and are commonly used as marker proteins for lipid microdomains. Yet almost a decade after their discovery, the function of reggies/ flotillins is still enigmatic. In this review we summarize the present state of knowledge on reggie/flotillin structure, localization and function, and discuss the role of the proteins in development and disease. Based on insights into reggie/flotillin function and by comparison with related proteins of the so-called SPFH (Stomatin/Prohibitin/ CMLS, Cell. Mol. Life Sci. 62 (2005) 2228-2240 1420-682X/05/202228-13 DOI 10.1007/s00018-005-5166-4 © Birkhäuser Verlag, Basel, 2005 Flotillin/HflK/C) protein family, including stomatin, podocin and prohibitin, we propose the existence of specific types of protein-defined microdomains which are sculpt by the clustering of individual SPFH proteins. As 'specialized rafts' similar to caveolae, these membrane domains provide platforms for the recruitment of multiprotein complexes. Since, under certain circumstances, reggie-2/flotillin-1 translocates to the nucleus, reggie/ flotillin microdomains are not only stable scaffolds but also dynamic units with their own regulatory functions.Key words. Lipid raft microdomains; signaling scaffolds; actin cytoskeleton; SPFH domain; stomatin; podocin; prohibitin; caveolae. Discovery of reggie/flotillins'Third time is a charm' the saying goes, and accordingly, reggie/flotillin proteins were independently 'discovered' three times. Madeleine Duvic and co-workers were the very first to discover part of one of the proteins during a screen for the antigen of the monoclonal antibody ECS-1 in 1994. They identified a complementary DNA (cDNA) coding for a N-terminally truncated version of reggie-1/flotillin-2 of 42 kDa (see below), which they called epidermal surface antigen (ESA) [1]. This name was later abandoned, as it was shown that this protein is not the true antigen recognized by ECS-1 [2]. In a screen for proteins upregulated in retinal ganglion cells during axon regeneration after optic nerve lesion in goldfish, we identified in 1997 two proteins of 47 kDa which we called reggie-1 and -2 [3,4]. In the same year Michael Lisanti's group identified two proteins associated with the 'floating' lipid raft fraction from mouse lung tissue which they called flotillin-1 (= reggie-2) and flotillin-2 (= reggie-1) [5]. Although flotillins became the more commonly used name for the proteins, we will stick with reggie-1 and -2, since we believe that our names and numbers are more appropriate in light of the physiological relevance of the two proteins. Structure of reggiesReggie proteins are highly conserved, with about 64% homology between fly and man [6,7]. Reggie-like proteins even exist in some bacteria, plants and fungi [8,9].

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Section: Subcellular Localization and Trafficking Of Reggiesmentioning

confidence: 95%

Section: Cellular Function Of Reggie Proteinsmentioning

confidence: 96%

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Scaffolding microdomains and beyond: the function of reggie/flotillin proteins

Langhorst

Reuter

Stuermer

2005

Cell. Mol. Life Sci.

288

273

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“…The position of the MM-associated proteins within the gradient was determined by immunoblotting for flotillin-1, a known MM marker 42,43 and showed flotillin-1 to be enriched in fractions 3-6, representing the 5-30% interface of the sucrose gradient ( Figure 1). In keeping with previous reports that the transferrin receptor is present in non-detergent-resistant membrane fractions and is solubilized under the above conditions, 44 this receptor was found in the soluble membrane fractions only (fraction 10; Figure 1).…”

Section: Flotillin-1 and Transferrin Receptor Distributionmentioning

confidence: 99%

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

et al. 2008

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The dorsolateral prefrontal cortex (dlpfc) is strongly implicated in the pathogenesis of schizophrenia (SCZ) and bipolar disorder (BPD) and, within this region, abnormalities in glutamatergic neurotransmission and synaptic function have been described. Proteins associated with these functions are enriched in membrane microdomains (MM). In the current study, we used two complementary proteomic methods, two-dimensional difference gel electrophoresis and one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis followed by reverse phase-liquid chromatography-tandem mass spectrometry (RP-LC-MS/MS) (gel separation liquid chromatography-tandem mass spectrometry (GeLC-MS/MS)) to assess protein expression in MM in pooled samples of dlpfc from SCZ, BPD and control cases (n = 10 per group) from the Stanley Foundation Brain series. We identified 16 proteins altered in one/both disorders using proteomic methods. We selected three proteins with roles in synaptic function (syntaxin-binding protein 1 (STXBP1), brain abundant membrane-attached signal protein 1 (BASP1) and limbic system-associated membrane protein (LAMP)) for validation by western blotting. This revealed significantly increased expression of these proteins in SCZ (STXBP1 (24% difference; P < 0.001), BASP1 (40% difference; P < 0.05) and LAMP (22% difference; P < 0.01)) and BPD (STXBP1 (31% difference; P < 0.001), BASP1 (23% difference; P < 0.01) and LAMP (20% difference; P < 0.01)) in the Stanley brain series (n = 20 per group). Further validation in dlpfc from the Harvard brain subseries (n = 10 per group) confirmed increased protein expression in SCZ of STXBP1 (18% difference; P < 0.0001), BASP1 (14% difference; P < 0.0001) but not LAMP (20% difference; P = 0.14). No significant differences in STXBP1, BASP1 or LAMP protein expression in BPD dlpfc were observed. This study, through proteomic assessments of MM in dlpfc and validation in two brain series, strongly implicates LAMP, STXBP1 and BASP1 in SCZ and supports the view of a neuritic and synaptic dysfunction in the neuropathology of SCZ.

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“…For example, lipid modification of Wnt proteins is crucial for their function, and lipidation of Drosophila Wnt-1 localizes this protein to specialized lipid raft domains (Willert et al, 2003;Zhai et al, 2004). Flotillin-1 has been implicated in axonal regeneration, insulin signaling, membrane scaffolding and cell polarity, phagocytosis, immune cell activation and a variety of signal transduction events in several adult cell types (e.g., Schulte et al, 1997;Baumann et al, 2000;Dermine et al, 2001;Salzer and Prohaska, 2001;Stuermer et al, 2001;Solomon et al, 2002;Rajendran et al, 2003;Slaughter et al, 2003;Neumann-Giesen et al, 2004). In neurons and astrocytes, Flotillins (also called Reggie in rat and goldfish) closely associate with fyn kinases and the GPI-linked proteins Thy1 and F3 (Stuermer et al, 2001) and are enriched at synapses (Kokubo et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Xenopus flotillin1, a novel gene highly expressed in the dorsal nervous system

Pandur

Dirksen

Moore

et al. 2004

Developmental Dynamics

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The two paralogues of the Xenopus flotillin1 gene (flotillin1A and flotillin1B), which encodes a putative membraneassociated protein, were cloned from egg, cleavage, and tadpole cDNA libraries. Both mRNAs are present during oogenesis and cleavage stages. After the onset of zygotic transcription, flotillin1 transcripts are first expressed throughout the embryonic ectoderm and become enhanced in the presumptive neural ectoderm as the neural plate forms. As the neural tube forms and differentiates, flotillin1 transcripts become enriched in the dorsal half, with particularly high expression in dorsal primary neurons. At early tail bud stages, there is additional expression in the paraxial mesoderm. At late tail bud stages, flotillin1A is expressed in branchial arch mesenchyme, the overlying branchial ectoderm and in dorsal somitic mesoderm, whereas flotillin1B expression is more restricted in the dorsal neural tube and head sensory structures. This report is the first comprehensive developmental description in any animal of the expression pattern of this gene, whose protein product in several systems plays important roles in signal transduction events. Developmental Dynamics 231:881-887, 2004.

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The flotillins are integral membrane proteins in lipid rafts that contain TCR-associated signaling components: implications for T-cell activation

Cited by 79 publications

References 61 publications

Scaffolding microdomains and beyond: the function of reggie/flotillin proteins

Scaffolding microdomains and beyond: the function of reggie/flotillin proteins

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

Xenopus flotillin1, a novel gene highly expressed in the dorsal nervous system

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