Caveolin-1/Caveolae are in Focus of Regulating EMT and MET

Abstract

During epithelial-mesenchymal transition (EMT) polarized epithelial cells undergo a complex proteomic remodelling, several biochemical and morphological changes converting them into mesenchymal-like cells. [1]. Besides of expressing mesenchymal markers (N-cadherin, vimentin, α-smooth muscle actin etc) they acquire the ability to produce extracellular matrix components, as well as metalloproteinases, inflammatorycytokines, fibrogenic and angiogenic factors [2]. Three types of EMTs have been distinguished so far: epithelial-mesenchymal transition during embryogenesis (type I), EMT associated with inflammation, wound healing, tissue regeneration and organ fibrosis (type II) and tumorigenesis (type III) [3]. EMT is triggered by extracellular signals including various cytokines, growth factors, extracellular matrix components. Transforming growth factorβ (TGFβ) family members are the most important regulators in this process. The TGFβ signalling pathways are generally divided into Smad-dependent and Smad-independent processes. When TGFβ binds to its primary serine/threonine kinase receptor (type II) it induces the formation of a heteroterameric receptor complex. Type II receptor thentrans phosphorylates (activates) the signalling receptor (type I) that can initiate Smad2/3 signalling pathway. The receptor internalization is required for the initiation of downstream signalling [4]. In addition to promoting the signalling process by transporting these molecules to the signalling organelles, the receptor-ligand internalization can control the number of receptors present on the cell surface. Thus, receptor internalization regulates the signalling, receptor turnover, the magnitude and duration of the events. In EMT clathrinmediated as well as caveolar endocytosis (internalization via caveolae) play an important role [5]. Caveolae are small omega-or flask-shaped plasma membrane invaginations, highly hydrophobic membrane domains (lipid rafts) containing a special protein, caveolin-1 [6,7]. It is generally accepted that endocytosis via caveolae directs the receptorligand complex to lysosomal and/or proteasomal degradation [8,9] which downregulates the receptors on the cell surface. Caveolin-1 downregulation together with caveolar internalization of TGFβ receptorsturns off the TGFβ signalling pathway,thereby blocking EMT.TGFβ can induce and/or promote EMT through a Smadindependent pathway as well. In response to TGFβ the type II TGFβ receptor can autophosphorylate tyrosine amino acids (Tyr259, 336 and 424) [10], and can undergo Src-mediated tyrosine phosphorylation as well [11,12]. Thetyrosine phosphorylated TGFβ receptor can activate MAP kinase (MEK) and ERK1/2. Members of the Ras/Raf/MEK/ ERK kinase cascades are present in caveolae and caveolin-1 promotes ERK activation. Kinase suppressor of Ras1 (KSR1) is a caveolin-1 interacting protein, and the KSR1-caveolin-1 interaction is required for the redistribution of MEK/ERK in caveolin-rich fractions, actually caveolin-1 facilitates the formation of KSR1/MEK/ERK complex.KSR1-...