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© Borgis - Postępy Nauk Medycznych 11/2011, s. 936-941
*Natalia Fedoryszak-Kuśka
Could membrane lipids influence the receptor tyrosine kinase activity? Epidermal growth factor receptor and its interactions with gangliosides**
Czy lipidy błonowe modyfikują aktywność receptorowych kinaz białkowych? Receptor epidermalnego czynnika wzrostu i jego oddziaływania z gangliozydami
Department of Biochemistry and Molecular Biology, Medical Center of Postgraduate Education, Warsaw
Head of Department: prof. dr hab. Barbara Czarnocka
Streszczenie
Błona komórkowa jest niezwykle skomplikowaną strukturą, w obrębie której ostatnio wyróżniono wyspecjalizowane fragmenty, zwane tratwami lipidowymi, odpowiedzialne za regionalizację procesów życiowych komórki. Tratwy lipidowe są kombinacją szeregu lipidów: cholesterolu, sfingolipidów, w tym glikosfingolipidów i szczególnych białek, wśród których wyróżniono liczne białka receptorowe. Wyniki wielu badań wykazały, że aktywność białek receptorowych jest zależna od glikosfingolipidów, a szczególnie od gangliozydów zarówno w warunkach fizjologicznych, jak i patologicznych. Wykazano, że białkami receptorowymi, których aktywność jest regulowana przez gangliozydy, są receptory fibroblastowego czynnika wzrostu (FGF), płytko-pochodnego czynnika wzrostu (PDGF), nerwowego czynnika wzrostu (NGF), insulinowego, a także epidermalnego czynnika wzrostu (EGF). Najciekawszy mechanizm regulacji aktywności białka receptorowego przez gangliozydy przedstawiono dla receptora epidermalnego czynnika wzrostu (EGFR). Wykazano, że aktywność EGFR jest uzależniona od składu gangliozydów występujących w jego otoczeniu. Zaobserwowano wzrost aktywności EGFR jeśli w jego otoczeniu znajdują się takie gangliozydy jak GM1 lub GD1a. Jednocześnie akumulacja gangliozydu GM3 w sąsiedztwie EGFR przyczynia się do spadku aktywności receptora. Wyjaśnienia wielorakość efektów oddziaływań między gangliozydami i EGFR szuka się w zależnościach w budowie cząsteczek gangliozydów i białka receptorowego. Na podstawie analizy struktury obu molekuł wykazano możliwość tworzenia bezpośrednich wiązań miedzy domeną zewnątrzbłonową EGFR a hydrolifowym fragmentem cząsteczki gangliozydu. Obecność tej bezpośredniej interakcji próbuje się wykorzystać w terapii inwazyjnych nowotworów.
Summary
Cell membrane is a complex structure. Recently great attention is devoted to specialized membrane fragments responsible for compartmentalization of cellular processes called lipid rafts. Lipid rafts are made of a combination of cholesterol, sphingolipids, including glycosphingolipids, and proteins among them a number of receptors. The glycosphingolipids, especially gangliosides, have been proven to play crucial roles in the regulation of biological functions of raft localized proteins under both physiological and pathological conditions. Gangliosides modulate activity of protein receptors activated by fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), insulin, and epidermal growth factor (EGF). One of the most interesting mechanism of regulation of receptor activity by gangliosides has been shown for epidermal growth factor receptor (EGFR). EGFR activity is dependent on ganglioside composition in its vicinity. Thus GM1 or GD1a gangliosides enhance EGFR activity while GM3 is a well-known EGFR inhibitor. Probably the different ways by which gangliosides influence the EGFR activity is associated with specific structures of both the ganglioside molecule and EGFR. Numerous studies proved direct interaction between these two types of molecules. This interaction could possibly prove to be crucial in the treatment of invasive cancers.
Introduction
Glycosphingolipids (GSLs) are ubiquitous components of all vertebrate cell membranes. They represent from less than 5% (erythrocytes) to more than 20% (myelin) of membrane lipids (1). Although GSLs have common schematic structure, they are highly heterogeneous group of lipids. With regard to their headgroups, the GSLs were divided into two groups: galactosphingolipids and glucosphingolipids (2). The sialic acid containing glucosphingolipids are the gangliosides (3).
It was observed that GSLs are not uniformly distributed in the membrane. Instead GSLs are clustered in structures called “lipid rafts”, which are defined as “areas in the membrane different in lipid composition from other membrane regions and characterized by a lateral organization dictated by the properties of their lipid composition. This has significant influence on large number of biological events” (4-10).
Gangliosides and membrane protein function
As it was already mentioned GSLs, including gangliosides, are lipid rafts components. Uneven distribution of gangliosides is probably the result of their specific structure. They have a hydrophobic long carbon chain residue (ceramide) and a hydrophilic oligosaccharide moiety (hydrophilic headgroup) (fig. 1A). The long saturated carbon chains of ceramide have unique biophysical properties, which allow self-aggregation and formation of “clusters” (1). The gangliosides hydrophilic oligosaccharides chains provide sites for interaction with extracellular molecules such as toxins, extracellular matrix components, adhesion molecules, receptors and enzymes on the surface of adjacent cells (trans interaction). Moreover gangliosides hydrophilic headgroups take part in lateral interaction (cis interaction) with receptors and enzymes in the same membrane (11).
Fig. 1. Gangliosides and lyso-gangliosides structures: A: GM3 – schematic and structural formula; B: lyso-GM3 structural formula; (Glc – glucose, Gal – galactose, NeuAc – neuraminic acid).
The interaction between gangliosides and proteins in lipid rafts are still not fully understood. It was proven that “cluster” of gangiosides is a less fluid part of the membrane, where membrane associated proteins could be confined. Within the lipid rafts there are lateral interactions between lipids and proteins. But also there are limited interactions between proteins associated with different lipid rafts (12).
It should be mentioned that only some proteins classes are highly concentrated in lipids rafts (13). The most popular motifs present in lipid rafts proteins are a glycophosphatidylinositol anchor or a lipid modifications of protein such as myristoylation or palmitoylation. Also transmembrane proteins are present in lipid rafts despite the modeling of transmembrane peptides that indicated in general that targeting to liquid-ordered phases is disfavored (12). These transmembrane proteins localized in the lipid rafts are growth factor receptors, including receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), insulin and epidermal growth factor (EGF) (13). It has been assumed that the trapping of certain proteins in lipid rafts might be somehow crucial to their biological role (14).
This hypothesis was confirmed by a wide-range of studies on the role of gangliosides in function of membrane protein receptors. The negative (inhibitory) and positive (activatory) effect of gangliosides on receptor proteins were observed. For example GM1, GM2, GD1a and GT1b cause inhibition of PDGFR phosphorylation (15-16) and GM3 reduces EGFR phosphorylation. In contrast enhancement of growth factor receptor phosphorylation has been observed with GD1a and GM1 for EGFR (17-19) and FGFR (20). The opposite effects were detected as a result of interactions between receptor and gangliosides, thus suggesting that the mechanism of these interactions is complex.
Probably, this situation results from several possibilities of binding between ganglioside molecules and proteins. The first option is the binding between ganglioside and proteins amino acid residues in the extracellular loops. The second is the binding between ganglioside headgroup and sugar residues in glycans of a glycosylated proteins. The last option is the hydrophilic binding with the oligosaccharide part of an anchor of GPI-anchored proteins (12). These three types of binding could induce different conformation changes in membrane protein, which probably would influence their biological functions.
EGFR function depends on gangliosides
The epidermal growth factor receptor (EGFR) belongs to a EGFR family that consists of four receptors. EGFR is a 170 kDa transmembrane glycoprotein that comprises of 1186 amino acids (21). EGFR resides as a monomer in lipid rafts. In the monomeric structure one can distinguish tree domains: an extracellular domain, a transmembrane domain, and a tyrosine kinase cytoplasmic domain. The extracellular domain is responsible for epidermal growth factor (ligand) binding whereas the cytoplasmic domain plays a crucial role in signal transduction. The EGFR monomers could form predimers in ligand independent (fig. 2A) or dependent way (fig. 2B). The consequence of ligand binding, dimerisation, and exit from the lipid rafts is the EGFR autophosphorylation and subsequently downstream signaling (14).
Fig. 2. The epidermal growth factor receptor (EGFR) activation. A: ligand independent dimer formation and B: ligand dependent dimer formation; (EGF – epidermal growth factor).
The EGFR activity could be modified in each step that occurs before, during, and after ligand binding. Gangliosides were proposed to act as modulators of EGFR activity. It was mentioned that ganglioside GM1 enhances the EGFR activity whereas GM3 was defined as a EGFR inhibitor. The mechanism of regulation of the EGFR activity by gangliosides was illustrated in previous sections.
GM3 and EGFR activity

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otrzymano: 2011-09-12
zaakceptowano do druku: 2011-10-17

Adres do korespondencji:
*Natalia Fedoryszak-Kuśka
Zakład Biochemii i Biologii Molekularnej Centrum Medyczne Kształcenia Podyplomowego
ul. Marymoncka 99, 01-813 Warszawa
tel.: (22) 569-38-15
e-mail: fedna@cmkp.edu.pl

Postępy Nauk Medycznych 11/2011
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