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

Abstract

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].

Flotillins play an essential role in Niemann-Pick C1-like 1-mediated cholesterol uptake

“…S1 C and D). Microscopic analysis showed that NPC1L1 specifically colocalized with flotillin-1 and flotillin-2 rather than caveolin-1, the caveolar lipid raft marker (12), or stomatin, another SPFH family member (8,9,11). It partially colocalized with GPI-anchored proteins and ganglioside GM1, two general lipid raft markers (Fig.…”

“…Here, we unravel an important role of flotillin-1 and flotillin-2, two homologous lipid raft proteins belonging to stomatin-prohibitin-flotillin-HflK/C (SPFH) domain family (8)(9)(10)(11), in NPC1L1-mediated cellular cholesterol uptake and biliary cholesterol reabsorption.…”

Ancient origin of reggie (flotillin), reggie-like, and other lipid-raft proteins: convergent evolution of the SPFH domain

“…Reggie-1 and reggie-2 subserve functions in the assembly of specific surface proteins and intracellular signal transduction components, leading to signaling across the plasma membrane and regulation of the actin cytoskeleton [17,18]. The broad evolutionary distribution of reggie/flotillin and reggie-like proteins across distant phyla suggest the requirement of an ancient basic function.…”

“…Additional lines of evidence such as co-immunoprecipitation, cross-linking and microscopy confirm the idea that reggie/ flotillin microdomains play an important role in cell-cell recognition, adhesion and signaling events [reviewed in refs. 17,18]. Reggies/flotillins are highly expressed in virtually all growing structures of the developing zebrafish, particularly in tissues actively undergoing rapid proliferation and differentiation [19].…”

Wnt Signaling from Development to Disease: Insights from Model Systems

“…Reggie-1 (Flotillin-2) is a cytoplasmic component of noncaveolin lipid microdomains (Babuke and Tikkanen 2007;Langhorst et al 2005). Reggie-1 loss strongly reduces longrange Wg targets but has no effect on shortrange targets (Katanaev et al 2008).…”