Flotillins: At the Intersection of Protein S-Palmitoylation and Lipid-Mediated Signaling

Abstract

Flotillin-1 and flotillin-2 are ubiquitously expressed, membrane-associated proteins involved in multifarious cellular events from cell signaling, endocytosis, and protein trafficking to gene expression. They also contribute to oncogenic signaling. Flotillins bind the cytosolic leaflet of the plasma membrane and endomembranes and, upon hetero-oligomerization, serve as scaffolds facilitating the assembly of multiprotein complexes at the membrane–cytosol interface. Additional functions unique to flotillin-1 have been discovered recently. The membrane-binding of flotillins is regulated by S-palmitoylation and N-myristoylation, hydrophobic interactions involving specific regions of the polypeptide chain and, to some extent, also by their oligomerization. All these factors endow flotillins with an ability to associate with the sphingolipid/cholesterol-rich plasma membrane domains called rafts. In this review, we focus on the critical input of lipids to the regulation of the flotillin association with rafts and thereby to their functioning. In particular, we discuss how the recent developments in the field of protein S-palmitoylation have contributed to the understanding of flotillin1/2-mediated processes, including endocytosis, and of those dependent exclusively on flotillin-1. We also emphasize that flotillins affect directly or indirectly the cellular levels of lipids involved in diverse signaling cascades, including sphingosine-1-phosphate and PI(4,5)P2. The mutual relations between flotillins and distinct lipids are key to the regulation of their involvement in numerous cellular processes.

SFPH proteins as therapeutic targets for a myriad of diseases

“…Similarly to PHBs, flotillins exist as 2 isoforms, flotillin-1 and flotillin-2, which are ubiquitously expressed scaffold proteins involved in various aspects of cell signaling, cytoskeleton remodeling, endocytosis, release of extracellular vesicles and protein trafficking. 43 To fulfill these functions, they directly interact with several proteins, including the EGF receptor, the kinases Lyn, Fyn, Lck, cRAF, MEK1, ERK2, cRAF, MEK1/2, ERK1/2, KSR1 the small GTPases Gαq, Rab11, β-catenin, γ-catenin, E-cadherin, N-cadherin, the adaptor protein ArgBP2, the adapter protein SORBS1 /CAP/Ponsin, the E3 ubiquitin-protein ligase Cbl, α-actinin or F-actin. As far as we know, no small molecules targeting flotillins has been discovered yet, but such agents could display interesting effects to treat several types of diseases, including cancers, immunological, cardiac and neurodegenerative disorders.…”

Flotillin-1 Interacts With and Sustains the Surface Levels of TRPV2 Channel

“…Flotillin-1 is preferentially associated with flotillin-2 in hetero-oligomeric complexes, forms membrane microdomains that serve as scaffolds facilitating the assembly of multiprotein complexes at the membrane-cytosol interface ( Zhao et al, 2011 ; Kwiatkowska et al, 2020 ). It was observed that flotillin-1 is associated with tyrosine-protein kinase Lyn and enhances its activity ( Kato et al, 2006 ).…”

Function of Platelet Glycosphingolipid Microdomains/Lipid Rafts

“…Flotillins bind the inner leaflet of a plasma membrane raft and serve as scaffolds facilitating the assembly of multiprotein complexes. Flotillin-1 and flotillin-2 have the same domain architecture, comprising two domains: the N-terminal SPFH domain and the C-terminal flotillin domain [98]. The SPFH and flotillin domains mediate inner membrane binding and oligomerization of flotillins, respectively.…”

“…Sphingosine binding is mediated by the SPFH domain of flotillins, but the exact identities of the hydrophobic sequences of the flotillins involved are not known. Flotillins also interact with numerous signaling proteins such as receptors, protein kinases, G proteins, and adaptors [98]. Therefore, flotillin-based microdomains can serve as platforms mediating the formation of multiprotein complexes and transmembrane signal transduction at the plasma membrane.…”