Caveolar-mediated Endocytosis Signaling


Pathway Description

Different mechanisms are available for the endocytic internalization of a variety of particles (molecules, viruses, bacteria...), including clathrin-mediated endocytosis, caveolar-mediated endocytosis, macropinocytosis and non-clathrin, non-caveolae endocytosis. Caveolar-mediated endocytosis plays a role in various cellular processes such as endocytosis, cellular signaling and lipid recycling. Caveolae are cholesterol- and sphingolipid-rich, flask-shaped invaginations of the plasma membrane, which are involved in the internalization of membrane components, extracellular ligands (insulin, albumin, EGF), viruses (Simian virus 40, Coxsackievirus) and bacterial toxins (cholera toxin). Although caveolae contain also several signaling molecules, growth factor receptors and flotillins, caveolin-1 is the major component of caveolae. This protein has the ability to bind cholesterol and form high molecular weight oligomers that self-associate to stabilize the caveolae. Under basal conditions, plasma membrane caveolae are anchored by filamin, which binds to caveolin-1 and to the actin cytoskeleton. Internalization of caveolae can be induced by numerous stimuli, including insulin, EGF, hyperosmotic and oxidative stress, cholera toxin, bacteria and viruses. It has been shown that the tyrosine phosphorylation of caveolin-1 plays an important role in caveolae dynamics and some of the stimuli mediate caveolin-1 phosphorylation through nonreceptor tyrosine kinases, such as c-Abl, Src and Fyn. Furthermore, caveolin-1 tyrosine phosphorylation is involved in integrin-regulated caveolae trafficking. Upon cell detachment from the extracellular matrix (ECM), phosphorylated caveolin-1 translocates from focal adhesions to caveolae, where it induces its internalization. In addition to caveolin-1, caveolae contain Dynamin 2, which is recruited to the neck of the flask-shaped caveolar indentations and facilitates the fission of the caveolar vesicle. After internalization, the caveolae move to the cytosol, where it can fuse with pre-existing structures called caveosomes, or with early endosomes in a Rab5-dependent manner. The caveolae can also engage in long-range trafficking mediated by microtubules and DYRK3. After binding to the plasma membrane via major histocompatibility (MHC) class I molecules, Simian virus 40 initiates a signaling cascade that leads to the depolarization of actin cytoskeleton and caveolae internalization. These primary caveolae fuse with the caveosomes, which are transported along microtubules to endoplasmic reticulum.