Annexin A6—A multifunctional scaffold in cell motility

Abstract

Annexin A6 (AnxA6) belongs to a highly conserved protein family characterized by their calcium (Ca)-dependent binding to phospholipids. Over the years, immunohistochemistry, subcellular fractionations, and live cell microscopy established that AnxA6 is predominantly found at the plasma membrane and endosomal compartments. In these locations, AnxA6 acts as a multifunctional scaffold protein, recruiting signaling proteins, modulating cholesterol and membrane transport and influencing actin dynamics. These activities enable AnxA6 to contribute to the formation of multifactorial protein complexes and membrane domains relevant in signal transduction, cholesterol homeostasis and endo-/exocytic membrane transport. Hence, AnxA6 has been implicated in many biological processes, including cell proliferation, survival, differentiation, inflammation, but also membrane repair and viral infection. More recently, we and others identified roles for AnxA6 in cancer cell migration and invasion. This review will discuss how the multiple scaffold functions may enable AnxA6 to modulate migratory cell behavior in health and disease.

Screening for Host Proteins Interacting with Escherichia Coli O157:H7 EspF using Bimolecular Fluorescence Complementation

“…The interaction with actin gave ANXA6 the capacity to rearrange the cytoskeleton and form membranecytoskeleton complexes [60]. ANXA6 may recruit complex protein-protein interactions to remodel the actin cytoskeleton, which is the vital middle chain for EspF's ability to destroy TJs.…”

“…It was reported that the EspFs of both EHEC and EPEC had the ability to bind to SNX9, but EHEC EspF had weaker binding to SNX9 compared with EPEC [59]; our results confirmed and extended the previous results that EHEC EspF can still bind to SNX9 when it is expressed in vitro. ANXA6 emerged as a multifunctional scaffold protein, and its ability to recruit signaling proteins, interact with actin and organize the cytoskeleton, and modulate membrane trafficking allowed it to be involved in many biological processes, such as membrane repair, cell proliferation, differentiation, survival and inflammation [60]. It has been suggested that ANXA6 cooperates with PKCα to downregulate EGFR signaling through elevation of PKCα and EGFR/PKCα membrane-targeting levels [61].…”

Ras Inhibitor CAPRI Enables Neutrophils to Chemotax Through a Higher-Concentration Range of Gradients

“…S2). p120 GAP is present in both human and mouse neutrophils but absent in HL60 cells (66) and its role has been implicated in cell migration (67, 68). While we revealed a major role of CAPRI in mediating the GPCR-mediated Ras adaptation in HL60 cells, it is also crucial to determine potentially roles of other RasGAP proteins in Ras adaptation and chemotaxis in primary mammalian neutrophils.…”

Annexin A6 as a cholesterol and nucleotide binding protein involved in membrane repair and in controlling membrane transport during endo- and exocytosis

“…The obtained results suggest that AnxA6 acts as a multifunctional scaffold protein and is able to recruit vast number of sig-naling proteins, modulates cholesterol transport and its distribution within the cell, and also regulates membrane transport through actin dynamics. These activities suggest that AnxA6 may contribute to the formation of specific protein complexes and membrane domains relevant in signal transduction, cholesterol homeostasis and endo-/exocytosis [Grewal et al 2017].…”

“…Annexin A6, as a cholesterol binding and multifunctional scaffold protein plays a crucial role in cell motility [Hayes et al 2004;Monastyrskaya et al 2009;Grewal et al 2017] and is implicated also in cell signaling [Koese et al 2013;Hoque et al 2014;Qi et al 2015;Cornely et al 2016;Raouf et al 2018]. Moreover, annexin A6 has been reported to regulate a formation of multifunctional signaling complexes at the membranes, affect membrane lateral organization, or influence cholesterol metabolism and dis-tribution, but also to participate in the vesicular transport both in endo-and exocytosis [Cubells et al 2007;Garcia-Melero et al 2016;Cairns et al 2017].…”