Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Flotillin-2 (FLOT2)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_646


Historical Background

Flotillin-2 was originally cloned in 1994 by Schroeder et al. by immunoscreening of a human keratinocyte cDNA library using the monoclonal antibody ECS-1 against cultured keratinocytes. ECS-1 stained human epidermis and caused keratinocyte detachment in vitro, leading to the hypothesis that ECS-1 antigen may play a role in epidermal cell adhesion. Therefore, the immunoisolated cDNA and deduced protein was termed “epidermal surface antigen” (ESA), reviewed in Langhorst et al. (2005) and Morrow and Parton (2005). Western blot analysis identified a 35 kDa protein. In 1997, Bickel et al. analyzed caveolin-rich membrane fractions from mouse lung and isolated a 45 kDa protein. Microsequencing yielded novel and ESA-specific peptide sequences. Degenerate primers were used for PCR of mouse lung cDNA, and the PCR product was then used as a probe for screening of a 3T3-L1 adipocyte cDNA library. The identified clone was characterized, and its sequence showed similarity to the ESA sequence (47% identity). An anti-peptide antibody identified a 47 kDa protein on Western blots. Because this protein was detected in floating, Triton X-100-insoluble membrane fractions together with caveolin-1 and ESA, it was termed “flotillin-1,” while the homologous ESA was renamed to “flotillin-2.” It turned out that the original, immunoisolated ESA was not the real ECS-1 antigen and not an epidermal surface antigen; therefore, this name was no longer appropriate. Also in 1997, Schulte et al. identified two proteins that were induced in regenerating fish retinal ganglion cell axons after injury and thus were named “reggie-1” and “reggie-2.” A striking 80% identity of fish reggie-1 and human flotillin-2 was recognized. In 1998, Lang et al. cloned the rat reggie proteins and found that rat reggie-1 is 99% identical to human flotillin-2, while rat reggie-2 is 98% identical to human flotillin-1. Reggie-1/flotillin-2 was identified at the plasma membrane of neurons and nonneuronal cells in non-caveolar micropatches co-clustering with reggie-2/flotillin-1 and GPI-anchored cell adhesion molecules. These micropatches localize along the axon and in lamellipodia and filopodia of growth cones. In 1999, Volonté et al. presented co-immunoprecipitation data that identified flotillin-1, flotillin-2, caveolin-1, and caveolin-2 in one complex. This led to the hypothesis that flotillins are resident components of caveolae; however, this hypothesis could not be verified by several groups, as reviewed in Langhorst et al. (2005). In 2001, Stuermer et al. identified clusters of reggies/flotillins with GPI-anchored proteins and Fyn kinase in non-caveolar plasma membrane microdomains of neurons and astrocytes. These microdomains had a diameter of less than 100 nm. In Jurkat cells, cross-linking of the GPI-anchored protein Thy-1 induced the colocalization of Thy-1, reggie/flotillin proteins, GM1, the T-cell receptor, and Fyn kinase, thus suggesting the formation of a raft-associated signal transduction center. Reggies/flotillins were also found in lysosomes, suggesting that the signaling complex becomes subject to degradation, reviewed in Langhorst et al. (2005). More details on the historical background can be found in Salzer and Prohaska (2011).

Protein Structure and Domain Organization

Mammalian flotillin-2 is a highly conserved, 48 kDa monotopic integral membrane protein of 428 amino acids that is divided into two large domains of similar size, an N-terminal “stomatin/prohibitin/flotillin/HflC/ K” (SPFH) domain, also known as “prohibitin homology domain” (PHB) or “band 7 domain,” and a C-terminal “flotillin domain” (Rivera-Milla et al. 2006). The N-terminal end of flotillin-2 contains a conserved hydrophobic region of about 30 amino acids that is associated with the cytoplasmic face of the bilayer but not spanning it. Both flotillins are not affected when proteinases are added to intact cells (Morrow and Parton 2005). It is not known if the hydrophobic region forms a “hairpin loop” similar to caveolin-1 or the related stomatin. Such a structure appears less likely in flotillin-2 due to several interspersed charged and hydrophilic residues. However, the N-terminus is truly membrane bound due to extensive modification by myristate at Gly-2 and palmitate at Cys-4, Cys-19, Cys-20, and probably Cys-38 (Neumann-Giesen et al. 2004; Rivera-Milla et al. 2006). In neurons, flotillin-2 is palmitoylated by the protein palmitoyltransferase, DHHC5 (Li et al. 2012). Downstream of the palmitoylation sites, the SPFH/PHB/Band 7 domain, is an ancient domain found in archaea and other prokaryotes; it comprises about 200 amino acids (Morrow and Parton 2005; Rivera-Milla et al. 2006). The solution structure of the mouse flotillin-2 SPFH domain was determined by NMR analysis (PDB ID: 1WIN; MMDB ID: 30602) and reveals a compact ellipsoid structure built from four β-strands on one side and four α-helices on the other. The crystal structure of the SPFH domain of an archaeal stomatin is surprisingly similar, and both structures can be superposed very well (PDB ID: 3BK6; MMDB ID: 62565). The function of this domain is not clear. Because many SPFH-domain proteins are lipid raft associated, it is possible that this domain mediates raft association (Morrow and Parton 2005). Indeed, the membrane-facing surface of this domain contains hydrophobic patches that would favor interactions with membrane lipids. Moreover, the interaction with cortical actin of one SPFH-domain α-helix (see Fig. 1) has been predicted and identified (Rivera-Milla et al. 2006). The C-terminal “flotillin domain” is characterized by three contiguous blocks of coiled-coil heptad motifs that contain multiple Glu-Ala repeats as well as charged residues at the heptad positions 2, 3, and 5 (Rivera-Milla et al. 2006). This domain is predicted to form dimers, trimers, and oligomers. Using chemical cross-linking, it was determined that flotillins form homo- or hetero-tetramers as building blocks of larger oligomeric complexes (Solis et al. 2007). Moreover, it was shown that flotillin-2 stabilizes flotillin-1. Apparently, flotillin-2 homo-oligomers are relatively stable but flotillin-1 homo-oligomers are not. Downregulation of flotillin-2 causes the concomitant loss of flotillin-1 due to proteasomal degradation but not vice versa (Solis et al. 2007). A conserved PDZ3-binding consensus was recognized near the C-terminal end and could be involved in regulating oligomerization of both flotillins (Rivera-Milla et al. 2006). A schematic model of the flotillin/reggie structural and functional domains is shown in Fig. 1.
Flotillin-2 (FLOT2), Fig. 1

Schematic model of flotillin. Schematic model of flotillin structural and functional domains. (a) Predicted 3D models of human flotillin-2/reggie-1 SPFH- and flotillin-domains, based on 1win.pdb and Swiss-Model server (swissmodel.expasy.org//SWISS-MODEL.html). α-helices (in yellow) are numbered in black, with the exception of α-helix 4, which is predicted to interact with actin and is numbered in red. β-sheets are drawn and numbered in blue, with the exception of human β-sheet 4 (located between β-1 and β-5, not shown). The amino (N) and carboxyl (C) ends are indicated by green letters and are truncated. (b) For comparison, the ribbon diagram of the human prohibitin-1 SPFH and C-terminal domain is shown, based on 1lu7.pdb. Numbering of α-helices and β-sheets as in A (β-1 to β-3 are not shown). (c) Two-dimensional model for the assembly of a reggie/flotillin microdomain, showing the proposed basic interaction between two adjacent flotillin/reggie molecules within a larger hetero-oligomer. Lipid rafts (blue) have distinct lipid compositions that differ from non-raft membrane domains (green). A hetero-tetrameric cluster of flotillin-2/reggie-1 and flotillin-1/reggie-2, highlighted in red, is expected to interact with the inner leaflet of the plasma membrane via its SPFH domain and acylation (jagged blue and red features). The C-terminal flotillin domain coiled-coil structures are assumed to stabilize the tetrameric complex (Figure and legend taken from Rivera-Milla et al. (2006) by courtesy of Springer Netherlands)


Flotillin-2 forms homo-oligomers as well as hetero-oligomers with flotillin-1 by interacting with the C-terminal coiled-coil domains (Neumann-Giesen et al. 2004; Solis et al. 2007). Hetero-oligomerization is essential for flotillin-1 stability, because flotillin-2 depletion induces flotillin-1 degradation by proteasomes (Solis et al. 2007). Hetero-oligomerization is further required for flotillin endocytosis (Frick et al. 2007; Babuke et al. 2009), a process that is regulated by phosphorylation via EGF receptor/Src (Neumann-Giesen et al. 2007) or Fyn kinase (Riento et al. 2009). Src phosphorylates Tyr-163 in flotillin-2 (Neumann-Giesen et al. 2007), and Fyn phosphorylates Tyr-163 in flotillin-2 and Tyr-160 in flotillin-1 (Riento et al. 2009). Both flotillins were found to associate with Niemann-Pick C1-like 1 (NPC1L1) in a complex with clathrin heavy chain (CHC) and AP2 subunit μ2 (Ge et al. 2011). The localization of this complex is cholesterol dependent. Cholesterol depletion causes transport of flotillins and NPC1L1 to the plasma membrane, whereas cholesterol replenishment leads to endocytosis of both. Thus, flotillins play a role in NPC1L1-mediated cellular cholesterol uptake and regulation of lipid levels. Flotillin knockdown dramatically decreased NPC1L1 endocytosis and cholesterol uptake and reduced the association between the CHC-AP2 complex and NPC1L1. Because the knockdown of CHC had no effect on the flotillin–NPC1L1 association, it appears that flotillins are required for recruitment of the CHC-AP2 complex to NPC1L1 and thus act upstream to mediate the internalization of NPC1L1 and cholesterol (Ge et al. 2011). The NPC1L1-binding drug ezetimibe was found to disrupt the flotillin–NPC1L1 complex. In this study, an important functional role of the flotillins was elucidated, namely, as mediators of cholesterol absorption via flotillin–NPC1L1-generated cholesterol-enriched membrane microdomains (Ge et al. 2011). Flotillins were also found to interact with the tetrameric N-methyl-d-aspartate receptor (NMDAR) by two-hybrid screening and co-immunoprecipitation with the subunits NR1, NR2A, and NR2B. The distal C-terminus of NR2B interacted with flotillin-1 and flotillin-2, whereas the C- terminus of NR2A bound only flotillin-1. Both flotillins were found to colocalize with NMDARs in hippocampal neurons (Swanwick et al. 2009). Moreover, both flotillins were shown to interact with the guanine-nucleotide-binding protein Gq subunit alpha (Gαq), independent of the Gαq-nucleotide-binding state (Sugawara et al. 2007). The flotillin N-terminal regions were essential for Gαq binding. Knockdown of flotillins, particularly flotillin-2, attenuated the UTP-induced activation of p38 mitogen-activated protein kinase (MAPK). Because the activation of MAPK depends on Src-family kinases and intact lipid rafts, these results suggest that flotillins mediate Gαq-induced MAPK activation through Src kinases in lipid rafts (Sugawara et al. 2007). In leukocytes, flotillin-2 interacts with P-selectin glycoprotein ligand-1 (PSGL-1), also known as SELPLG or CD162 (Rossy et al. 2009). When neutrophils are activated, flotillins rapidly form caps and later accumulate in the uropods of the polarized cells. While PSGL-1 accumulates in the uropods concomitantly, other uropod components such as CD43 and ERM proteins accumulate at a slower pace. Flotillins accumulate in uropods even in the absence of PSGL-1, indicating that PSGL-1 accumulation depends on flotillins (Rossy et al. 2009). This study was extended by using neutrophils from the flotillin-1 knockout mouse (Ludwig et al. 2010). They found that flotillin-2 was affected by the loss of flotillin-1, by showing weak, uniform staining of the plasma membrane and absence from detergent-resistant membranes. Importantly, the recruitment of flotillin-1-deficient neutrophils toward the chemoattractant fMLP was strongly reduced. Immunoisolation of tagged flotillin-2 followed by mass spectrometry of co-isolated proteins revealed the association of flotillin-2 with cytoskeletal proteins such as α- and β-spectrin and myosin IIa (Ludwig et al. 2010). The authors conclude that this association is important for neutrophil migration, uropod formation, and regulation of myosin IIa. More details on flotillin-2 interactions are described in Salzer and Prohaska (2011). Both flotillins interact directly with gamma-catenin, specifically with the Armadillo domains 6–8, and thereby regulate epithelial cell–cell adhesion (Kurrle et al. 2013). Flotillin-1 and -2 are also partners of large cadherin complexes; they are localized to cell–cell junctions in a cadherin-dependent manner and associate with F-actin bundles (Guillaume et al. 2013). The role of flotillins in intercellular adhesion was recently reviewed (Bodin et al. 2014). The interaction of flotillins with Rab11a and SNX4 indicates that flotillins are regulating the tubulovesicular recycling compartment (Solis et al. 2013). In human keratinocyte desmosomes, flotillins interact with the cytoplasmic tails of desmogleins, particularly desmoglein-3, while loss of flotillin expression results in weakened desmosomal adhesion (Völlner et al. 2016).

A list of described interaction partners is shown in Table 1.
Flotillin-2 (FLOT2), Table 1

Flotillin-2 (flot2) and flotillin-2 interaction partners

Interacting protein





Plasma membrane lipid rafts


Flotillin-2 is essential for flotillin-1 stability

Fyn kinase

Lipid rafts

Tyr phosphorylation

Induces endocytosis


Plasma membrane lipid rafts

Cholesterol endocytosis and transport

Involves clathrin heavy chain and AP2

NMDAR (N-methyl-d-aspartate receptor)

Neuronal plasma membrane

Glutamate-binding calcium channel

NR2A/B subunits bind to SPFH domain


Lipid rafts

Gαq-induced p38 MAPK activation

Depends on Src-family kinases

PSGL-1 (P-selectin glycoprotein ligand 1)

Plasma membrane

Involved in the polarization of neutrophils

Both flotillins and PSGL-1 accumulate in uropods

Alpha- and beta-spectrin

Plasma membrane

Neutrophil uropod formation

Both flotillins, PSGL-1, spectrin, and myosin IIa are needed for uropod formation

Myosin IIa

Plasma membrane

Neutrophil uropod formation

Both flotillins, PSGL-1, spectrin, and myosin IIa are needed for uropod formation


Erythrocyte membrane

Involved in NO signaling

Upregulation of arginase activity

PrPc (prion protein)

Plasma membrane, lipid-rich vesicles

Clustering at cell–cell contacts, focal adhesions

Complex with both flotillins

EGF receptor

HeLa cells

Activation of EGFR

Regulation of MAPK pathway activation


Adherence junctions

Cell–cell adhesion

Binding of flotillins to the Armadillo domains 6–8

Cadherin complexes

Cell–cell junctions

Cell–cell adhesion

Binding to large cadherin complexes and associated F-actin

Rab11a and SNX4

Recycling endosomes

Regulation of the recycling compartment

Direct interaction with Rab11a and SNX4


Desmosomes of human keratinocytes

Desmosomal adhesion complex

Binding to the cytoplasmic tails of desmogleins

Cellular and Subcellular Localization

Flotillin-2 is expressed ubiquitously in tissues and diverse cell types. Gene expression analyses by quantitative PCR of human and mouse (Mouse Genome Informatics MGI:103309) tissues have shown the expression in all tissues. In particular, flotillin-2 is highly expressed in hematopoietic cells (BioGPS GeneAtlas U133A, 201350_at), adipose tissue, spinal cord, and dorsal root ganglia (BioGPS GeneAtlas MOE430, 1417544_a_at). In cells, it is localized to the plasma membrane and internal vesicles such as Golgi vesicles, late endosomes and lysosomes (Neumann-Giesen et al. 2007; Langhorst et al. 2008), centrosomes (Langhorst et al. 2005), and recycling endosomes (Solis et al. 2013). At the plasma membrane, flotillin-2 is found in filopodia and lamellipodia, particularly when overexpressed (Neumann-Giesen et al. 2004; Langhorst et al. 2008). Flotillin hetero-oligomers in plasma membrane microdomains are endocytosed (Frick et al. 2007; Neumann-Giesen et al. 2007; Babuke et al. 2009; Riento et al. 2009) and apparently recycle back to the plasma membrane (Langhorst et al. 2008). Endocytosis takes place either in a clathrin- and caveolin-independent way (Riento et al. 2009) or in association with clathrin and NPC1L1 (Ge et al. 2011). Eventually the flotillin hetero-oligomeric complexes are transferred to the late endosomal compartment. In various cell types, flotillins are localized to recycling endosomes, late endosomes, multivesicular bodies, exosomes, lysosomes, phagosomes, and lipid droplets (Langhorst et al. 2005). As to the mechanism of flotillin endocytosis, there are apparently two mechanisms used depending on the cargo or function, either a clathrin-dependent or clathrin-independent pathway. The role of clathrin and dynamin in flotillin trafficking has been studied recently (Meister et al. 2014) showing that the pathways intersect also with the recycling pathway. In hematopoietic cells, flotillins are asymmetrically localized in stable, preassembled platforms of the plasma membrane, to which signaling components are recruited on activation (Rajendran et al. 2003). In chemoattracted neutrophils, flotillin microdomains accumulate rapidly in the uropod (Rajendran et al. 2009; Rossy et al. 2009) due to specific interaction with the cytoskeletal proteins α- and β-spectrin and myosin II (Ludwig et al. 2010). The role of flotillin microdomains in signaling, cytoskeletal regulation, and endocytosis was reviewed and discussed recently (Otto and Nichols 2011; Meister and Tikkanen 2014).

Regulation of Expression and Activity

In fish and mammals, both flotillins are upregulated in retinal ganglion cells during axon regeneration after optic nerve section, reviewed in Langhorst et al. (2005). Flotillin-2 expression is essential for flotillin-1 stability (Solis et al. 2007), and flotillin-1 expression also correlates with flotillin-2 expression (Ludwig et al. 2010). Both flotillins co-assemble at the plasma membrane in roughly equal amounts and act together to generate microdomains (Frick et al. 2007), which are endocytosed after Fyn-dependent tyrosine phosphorylation (Riento et al. 2009). Deletion of flotillin-1 apparently results in destruction of flotillin microdomains (Ludwig et al. 2010). Flotillin-2 was found to be a direct transcriptional target of the p53 family members p73 and p63 (Sasaki et al. 2008) due to a specific response element in the human FLOT2 gene. Expression of flotillin-2 was upregulated by p73 or p63 but not by p53. Moreover, transcription was activated in response to cisplatin but dependent on endogenous p73. siRNA, designed to target p73, silenced endogenous p73 and abolished the induction of flotillin-2 transcription following cisplatin treatment. A p73-/p63-binding site located upstream of the FLOT2 gene was identified and found to be responsive to the p53 family members. The flotillin-2 knockdown inhibited p63-mediated STAT3 activation. These data reveal a novel link between the p53 family and signal transduction via lipid rafts (Sasaki et al. 2008).

Overexpression of flotillin-2 was found in many carcinoma tissues (Banning et al. 2014). In nasopharyngeal carcinoma (NPC), flotillin-2 expression is positively associated with NPC metastasis. When flotillin-2 expression was inhibited in a highly metastatic NPC cell line, malignancy was impaired, whereas overexpression in a nonmalignant NPC cell line increased malignancy (Liu et al. 2015). In NPC cells with inhibited flotillin-2 expression, the NF-κB and PI3K/Akt3 pathways were inactivated, whereas in flotillin-2 overexpressing cells, enhanced NF-κB and PI3K/Akt3 activities were observed. Thus, flotillin-2 exerts a pro-neoplastic role through NF-κB and PI3K/Akt3 signaling in NPC cells and is involved in tumor progression and metastasis (Liu et al. 2015).

In Drosophila, Flotillin-2 was identified along with Src42A and Duox in a search for wound response genes. These genes were found to delimit the wound-induced transcriptional responses to a local zone of epidermal cells (Juarez et al. 2011). In Bacillus subtilis, the flotillin homologue FloT was found to interact with the membrane-bound sensor kinase KinC. This kinase activates biofilm formation in response to the self-produced signal, surfactin. The scaffold activity of FloT facilitates dimerization of KinC into its active form. The selective binding of FloT to KinC prevents the occurrence of unspecific aggregation between KinC and other proteins (Schneider et al. 2015). Flotillins appear to play an important role in prokaryotes in promoting effective binding of signaling proteins with their correct protein partners.

Variants and Mutants

There are three flotillin-2 isoforms described in the UniProtKB/Swiss-Prot database, accession number Q60634 (FLOT2_MOUSE). Isoform 1 (Q60634-1) has been chosen as the “canonical” sequence. Isoform 2 (Q60634-2) shows eight amino acid exchanges within the region of residues 50–68, the cause of which is unknown, and isoform 3 (Q60634-3) is missing the N-terminal 49 residues. The formation of isoform 3 may be caused by alternative splicing (skipping of exon 4, which is the first coding exon) and alternative translation initiation at Met-50. In Drosophila, flotillin-2 loss of function results in reduced spreading of the morphogens Wnt and Hedgehog (Hh), whereas its overexpression stimulates secretion of Wnt and Hh and expands their diffusion. The resulting changes in the morphogen gradients differently affect the short- and long-range targets. Apparently, flotillin-2 is an important component of the Wnt and Hh secretion pathway dedicated to formation of the mobile pool of these morphogens (Katanaev et al. 2008). In N2a neuroblastoma cells, the expression of a trans-negative flotillin-2 deletion mutant (R1EA), which interferes with flotillin oligomerization, inhibits insulin-like growth factor-induced neurite outgrowth, and impairs in vitro differentiation of primary rat hippocampal neurons (Langhorst et al. 2008). This mutant strongly perturbed Rac1 and Cdc42 activation caused by impaired recruitment of flotillin-associated CAP/ponsin to focal contacts.


Flotillin-2, also known as reggie-1, is a highly conserved, oligomeric, lipid-raft-associated, integral membrane protein of 48 kDa that is widely expressed in different tissues and cell types. It is associated with the cytosolic side of the plasma membrane and endosomes due to myristoylation, palmitoylation, and hydrophobic interaction. Flotillin-2 is mainly found in a hetero-oligomeric complex with its homologue flotillin-1, also known as reggie-2. Both flotillins/reggies are members of the SPFH (stomatin/prohibitin/flotillin/HflC/K) superfamily, also termed PHB (prohibitin homology domain) superfamily. Hetero-oligomerization is required for endocytosis of flotillin membrane microdomains either in a clathrin- and caveolin-independent way, such as Fyn-kinase-regulated endocytosis of GPI-anchored proteins, or in a clathrin-dependent way, such as cholesterol uptake mediated by Niemann-Pick C1-like 1 (NPC1L1). In neurons, flotillins/reggies control axon growth and growth cone elongation by coordinating the assembly of signaling complexes that regulate cortical cytoskeleton remodeling. In neutrophils, flotillin interaction with cytoskeletal components is required for normal migration and uropod formation. Flotillin microdomains thus constitute scaffolding platforms interacting with signaling components, cytoskeleton, and/or membrane proteins in various cellular processes. Recently, a great number of clinical studies on cancer patients have shown that flotillin-2 upregulation correlates with enhanced malignancy, metastasis, and poor patient survival.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Max F. Perutz Laboratories (MFPL)Medical University of ViennaViennaAustria