Annexin A6—Linking Ca2+ signaling with cholesterol transport

• Published in: Biochimica et biophysica acta. Molecular cell research 2011-05, Vol.1813 (5), p.935-947
• Main Authors: Enrich, Carlos, Rentero, Carles, de Muga, Sandra Vilà, Reverter, Meritxell, Mulay, Vishwaroop, Wood, Peta, Koese, Meryem, Grewal, Thomas
• Format: Article
• Language: English
• Subjects: Actin; Annexin A6; Caveolae; Caveolin-1; Cholesterol; cPLA2; PKCα; Ras/MAPK
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2010.09.015

Annexin A6 (AnxA6) belongs to a conserved family of Ca2+-dependent membrane-binding proteins. Like other annexins, the function of AnxA6 is linked to its ability to bind phospholipids in cellular membranes in a dynamic and reversible fashion, in particular during the regulation of endocytic and exocytic pathways. High amounts of AnxA6 sequester cholesterol in late endosomes, thereby lowering the levels of cholesterol in the Golgi and the plasma membrane. These AnxA6-dependent redistributions of cellular cholesterol pools give rise to reduced cytoplasmic phospholipase A2 (cPLA2) activity, retention of caveolin in the Golgi apparatus and a reduced number of caveolae at the cell surface. In addition to regulating cholesterol and caveolin distribution, AnxA6 acts as a scaffold/targeting protein for several signaling proteins, the best characterized being the Ca2+-dependent membrane targeting of p120GAP to downregulate Ras activity. AnxA6 also stimulates the Ca2+-inducible involvement of PKC in the regulation of HRas and possibly EGFR signal transduction pathways. The ability of AnxA6 to recruit regulators of the EGFR/Ras pathway is likely potentiated by AnxA6-induced actin remodeling. Accordingly, AnxA6 may function as an organizer of membrane domains (i) to modulate intracellular cholesterol homeostasis, (ii) to create a scaffold for the formation of multifactorial signaling complexes, and (iii) to regulate transient membrane–actin interactions during endocytic and exocytic transport. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. ►Cholesterol modulates the membrane binding and intracellular distribution of AnxA6. ►AnxA6-induced alterations in cholesterol transport and caveolin export from the Golgi. ►AnxA6 stimulates the membrane recruitment of p120GAP to modulate Ras and Raf-1 activity. ►AnxA6 inhibits Ras signaling in breast cancer cells. ►AnxA6 overexpression stabilizes cortical actin.