Disease relevance of FLOT2

• Flot-2 protein and mRNA were increased in tumorigenic and metastatic melanoma cell lines in vitro, and the immunostaining intensity increased substantially across a tissue array of melanocytic lesions [1].
• Flot-2 binds to PAR-1, a known upstream mediator of major signal transduction pathways implicated in cell growth and metastasis, and may thereby influence tumor progression [1].
• The ESA gene is conserved in all mammalian species examined and has been localized to human chromosome 17 (M17S1) in the same region as the gene for von Recklinghausen neurofibromatosis [2].
• Reggie-1 and reggie-2 are homologous to 35x10(3) Mr ESA (human epidermal surface antigen) but are here identified as neuronal surface proteins, present on newly differentiated ganglion cells at the retinal margin and which are reexpressed in mature ganglion cells upon injury and during axonal regeneration [3].
• ECS-1 shares characteristics with human pemphigus antibodies [4].

High impact information on FLOT2

• We further confirmed that the translocated CD45 bound to IL-6Ralpha, Lyn, and flotillin-2, and this was followed by the dephosphorylation of the negative regulatory Tyr507 of Lyn [5].
• The lipid-raft marker proteins flotillin-1 and flotillin-2 were also present in platelets but excluded from alpha granules [6].
• Up-regulation of Flotillin-2 is associated with melanoma progression and modulates expression of the thrombin receptor protease activated receptor 1 [1].
• Flot-2 transfection transformed SB2 melanoma cells from nontumorigenic, nonmetastatic to highly tumorigenic and metastatic in a nude mouse xenograft model [1].
• Up-regulation of PAR-1 was additionally confirmed in SB2-flot-2 cells and melanoma cell lines [1].

Biological context of FLOT2

• Flotillin 2 (flot-2) is a highly conserved protein isolated from caveolae/lipid raft domains that tether growth factor receptors linked to signal transduction pathways [1].
• Role of EGF-induced tyrosine phosphorylation of reggie-1/flotillin-2 in cell spreading and signaling to the actin cytoskeleton [7].
• Among acetyltransferases, the MYST family enzyme Esa1p is distinguished for its essential function and contribution to transcriptional activation and DNA double-stranded break repair [8].
• Here we report that Esa1p also plays a key role in silencing RNA polymerase II (Pol II)-transcribed genes at telomeres and within the ribosomal DNA (rDNA) of the nucleolus [8].
• Esa1p is enriched within the rDNA, as is the NAD-dependent protein deacetylase Sir2p, and the acetylation levels of key Esa1p histone targets are reduced in the rDNA in esa1 mutants [8].

Anatomical context of FLOT2

• When ECS-1 MoAb was used to screen a keratinocyte expression library, a unique cDNA was identified that predicted a 42-kDa globular protein of unknown function [9].
• In order to determine whether the cDNA predicted protein and ECS-1 antigen were identical, we compared ECS-1 with the immunoreactivity of a new antibody raised to the cDNA fusion protein in epidermis and cultured cells [9].
• Interestingly, the raft proteins flotillin-1 and flotillin-2 are not found in the vesicles but remain in the red cell membrane [10].
• The 2.5-kilobase ESA mRNA is expressed in cultured keratinocytes, melanocytes, fibroblasts, carcinoma, and melanoma cell lines [2].
• A significant portion of erythrocyte DRMs enriched in reported lipid raft markers, such as flotillin-1, flotillin-2 and GM1, is anchored to the spectrin membrane-skeleton via electrostatic interactions that can be disrupted by the simultaneous increase in pH and ionic strength of the solubilization medium [11].

Associations of FLOT2 with chemical compounds

• The ESA protein appears to consist of an NH2-terminal hydrophobic region with mixed alpha and beta structure followed by a more hydrophilic COOH-terminal region which is very rich in alpha-helix [2].
• The relative potencies of GC drugs as inhibitors of IL-1beta (10 pM)-stimulated ESAP-gene activation were fluticasone> beclomethasone>dexamethasone, with IC50 values of 0.13, 1.1 and 2.7 nM respectively [12].
• To investigate possible mechanisms for steroid inhibition, a reporter gene (ESAP) was constructed, comprising the cytokine responsive region of the E-selectin gene (nt -383 to +81) coupled to alkaline phosphatase (AP) [12].
• We therefore established a staining protocol using beta-mercaptoethanol as thiol binding site competitor resulting in a specific staining of tetracysteine-tagged reggie-1/flotillin-2 of adequate signal to noise ratio, so that the more toxic and inconvenient ethanedithiol could be avoided [13].
• Based on co-association of signalling molecules, such as Src kinases and phosphatases, we propose that the polycystin multiprotein complex is embedded in a cholesterol-containing signalling microdomain specified by flotillin-2, which is distinct from classical light-buoyant-density, detergent-resistant domains [14].

Other interactions of FLOT2

• In uncapacitated sperm, 51% of the CD59, 41% of the GM1, and 90% of the flotillin-2 were found in the raft fraction [15].
• We demonstrate for the first time by biochemical methods the existence of sphingolipid-cholesterol-enriched domains in human and dog thyroid follicular cells that contain caveolin, flotillin-2, and the insulin receptor [16].
• Flotillin-2, fli-1, pim-3 and ezrin have previously been reported to be associated with tumor metastasis and progression [17].

Analytical, diagnostic and therapeutic context of FLOT2

• Sequence analysis reveals that the 379 amino acid ESA has a molecular mass of about 41.7 kDa and an alpha-helix-rich secondary conformation [2].
• Flotillin-2 was assessed by immunoblotting as a marker for lipid rafts [18].

References