# ANXA6

## Overview
The ANXA6 gene encodes annexin A6, a member of the annexin family of proteins, which are characterized by their ability to bind phospholipids in a calcium-dependent manner. Annexin A6 is a multifunctional protein involved in various cellular processes, including membrane trafficking, signal transduction, and cytoskeletal interactions. Structurally, annexin A6 is unique due to its bilobular configuration, which allows it to interact flexibly with cellular membranes (Buzhynskyy2009AnnexinA6; AvilaSakar2000MembraneBound). Functionally, it plays a critical role in regulating signaling pathways such as those involving the epidermal growth factor receptor (EGFR) and Ras, as well as in maintaining cholesterol homeostasis and calcium signaling (Enrich2011Annexin; Grewal2010Annexin). Annexin A6's interactions with other proteins, such as actin and spectrin, further underscore its importance in cellular dynamics and motility (Enrich2011Annexin; Grewal2017Annexin). Clinically, alterations in ANXA6 expression have been associated with various cancers, highlighting its potential as a biomarker and therapeutic target (Wu2021Analysis; Sun2020ANXA6).

## Structure
Annexin A6 (ANXA6) is a unique member of the annexin family, characterized by its bilobular structure, which consists of two annexin core modules connected by a 40 amino-acid linker segment (Buzhynskyy2009AnnexinA6). Each lobe of ANXA6 is equivalent to a regular four-domain annexin, making the entire molecule similar to two annexins fused together (AvilaSakar2000MembraneBound). This structure allows ANXA6 to exhibit flexibility, enabling it to adopt various conformations when interacting with membranes (AvilaSakar2000MembraneBound).

The protein's tertiary structure is influenced by calcium ion concentration, which affects its membrane-binding properties. At low calcium concentrations, ANXA6 binds to membranes using its two coplanar annexin modules, while at high calcium concentrations, it can bind two adjacent phospholipid membranes (Buzhynskyy2009AnnexinA6). ANXA6 also contains a nucleotide-binding site, with specific amino acid residues involved in binding GTP and ATP, suggesting a role in nucleotide-dependent processes (BandorowiczPikula2003A).

ANXA6 may undergo post-translational modifications such as phosphorylation, and splice variants can result in isoforms with different functional properties. The protein's structure and flexibility are crucial for its roles in cellular processes like endocytosis and ion channel regulation (AvilaSakar2000MembraneBound).

## Function
Annexin A6 (ANXA6) is a calcium-dependent phospholipid-binding protein involved in various cellular processes. In healthy human cells, ANXA6 plays a crucial role in regulating the epidermal growth factor receptor (EGFR) and Ras signaling pathways, which are important for cell proliferation and differentiation. It acts as a scaffold for signaling proteins, targeting p120GAP to downregulate Ras activity and involving protein kinase C (PKC) in HRas and possibly EGFR pathways (Enrich2011Annexin; Grewal2010Annexin).

ANXA6 is also involved in cholesterol homeostasis by sequestering cholesterol in late endosomes, which reduces cholesterol levels in the Golgi and plasma membrane. This affects the activity of cytoplasmic phospholipase A2 and the formation of caveolae, small invaginations in the plasma membrane (Enrich2011Annexin; Grewal2010Annexin). ANXA6's interaction with the actin cytoskeleton stabilizes the cortical actin, reducing store-operated calcium entry (SOCE) and influencing calcium homeostasis (Monastyrskaya2009Plasma).

ANXA6 is active in various cellular compartments, including the plasma membrane, endosomes, and caveolae/membrane rafts, where it modulates membrane-actin interactions and intracellular cholesterol distribution, impacting processes such as endocytosis, exocytosis, and cell migration (Enrich2011Annexin; Grewal2010Annexin).

## Clinical Significance
Alterations in the expression of the ANXA6 gene have been implicated in various cancers. In bladder cancer, ANXA6 mRNA levels are significantly decreased in tumor tissues compared to normal tissues. However, higher expression of ANXA6 is associated with muscle-invasive bladder cancer (MIBC) and correlates with advanced clinical stages, indicating a poor prognosis for patients with elevated ANXA6 levels (Wu2021Analysis). In cervical cancer, ANXA6 acts as a tumor suppressor by inducing autophagy. Its downregulation is linked to poor survival outcomes, and its expression is associated with the suppression of tumorigenesis through autophagy induction (Sun2020ANXA6).

In head and neck squamous cell carcinoma (HNSCC), ANXA6 is highly expressed in tumors with lymphatic metastasis, correlating with poor clinical outcomes. Knockdown of ANXA6 reduces tumor growth and metastasis, suggesting its role in cancer progression (Wang2023ANXA6TRPV2). In breast cancer, ANXA6 influences cell adhesion and motility, with its expression being crucial for the invasiveness of carcinoma cells. Reduced ANXA6 expression is linked to enhanced cell proliferation and motility, indicating its role in cancer progression (Sakwe2011Annexin). These findings highlight ANXA6's potential as a biomarker and therapeutic target in various cancers.

## Interactions
Annexin A6 (ANXA6) is involved in various protein interactions that influence cellular processes. It binds to actin filaments in a calcium-dependent manner and interacts with α-actinin, co-localizing with F-actin at the plasma membrane, which is crucial for cell motility, spreading, and adhesion (Grewal2017Annexin). ANXA6 also interacts with spectrin to recruit calpain I, facilitating the cleavage of the spectrin-actin cytoskeleton and promoting endocytic vesicle entry at the plasma membrane (Enrich2011Annexin).

ANXA6 acts as a scaffold for signaling proteins, targeting p120GAP to downregulate Ras activity and stimulating PKC involvement in HRas and possibly EGFR pathways (Enrich2011Annexin). It interacts with the EGF receptor, p120GAP, H-Ras, PKCa, and other signaling proteins, influencing processes like Ras inactivation and actin remodeling (Cornely2011Annexin). ANXA6 recruits PKCα to the plasma membrane, inhibiting EGF receptor tyrosine phosphorylation and affecting receptor recycling (Cornely2011Annexin).

ANXA6 also interacts with the EspF protein from Enterohemorrhagic Escherichia coli, leading to tight junction disruption in host cells (Hua2020Enterohemorrhagic). These interactions highlight ANXA6's role as a multifunctional scaffold in cellular signaling and membrane dynamics.


## References


[1. (Sun2020ANXA6) Xin Sun, Yuhan Shu, Mengting Xu, Jiukun Jiang, Liming Wang, Jigang Wang, Dongsheng Huang, and Jianbin Zhang. Anxa6 suppresses the tumorigenesis of cervical cancer through autophagy induction. Clinical and Translational Medicine, October 2020. URL: http://dx.doi.org/10.1002/ctm2.208, doi:10.1002/ctm2.208. This article has 21 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/ctm2.208)

[2. (Monastyrskaya2009Plasma) Katia Monastyrskaya, Eduard B. Babiychuk, Andrea Hostettler, Peta Wood, Thomas Grewal, and Annette Draeger. Plasma membrane-associated annexin a6 reduces ca2+ entry by stabilizing the cortical actin cytoskeleton. Journal of Biological Chemistry, 284(25):17227–17242, June 2009. URL: http://dx.doi.org/10.1074/jbc.m109.004457, doi:10.1074/jbc.m109.004457. This article has 57 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m109.004457)

[3. (Buzhynskyy2009AnnexinA6) Nikolay Buzhynskyy, Marcin Golczak, Joséphine Lai-Kee-Him, Olivier Lambert, Béatrice Tessier, Céline Gounou, Rémi Bérat, Anne Simon, Thierry Granier, Jean-Marc Chevalier, Serge Mazères, Joanna Bandorowicz-Pikula, Slawomir Pikula, and Alain R. Brisson. Annexin-a6 presents two modes of association with phospholipid membranes. a combined qcm-d, afm and cryo-tem study. Journal of Structural Biology, 168(1):107–116, October 2009. URL: http://dx.doi.org/10.1016/j.jsb.2009.03.007, doi:10.1016/j.jsb.2009.03.007. This article has 44 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.jsb.2009.03.007)

[4. (Wang2023ANXA6TRPV2) Min Wang, Min Pan, Yanshi Li, Tao Lu, Zhihai Wang, Chuan Liu, and Guohua Hu. Anxa6/trpv2 axis promotes lymphatic metastasis in head and neck squamous cell carcinoma by inducing autophagy. Experimental Hematology & Oncology, May 2023. URL: http://dx.doi.org/10.1186/s40164-023-00406-1, doi:10.1186/s40164-023-00406-1. This article has 5 citations.](https://doi.org/10.1186/s40164-023-00406-1)

[5. (Cornely2011Annexin) Rhea Cornely, Carles Rentero, Carlos Enrich, Thomas Grewal, and Katharina Gaus. Annexin a6 is an organizer of membrane microdomains to regulate receptor localization and signalling. IUBMB Life, 63(11):1009–1017, October 2011. URL: http://dx.doi.org/10.1002/iub.540, doi:10.1002/iub.540. This article has 50 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/iub.540)

[6. (Sakwe2011Annexin) Amos M. Sakwe, Rainelli Koumangoye, Bobby Guillory, and Josiah Ochieng. Annexin a6 contributes to the invasiveness of breast carcinoma cells by influencing the organization and localization of functional focal adhesions. Experimental Cell Research, 317(6):823–837, April 2011. URL: http://dx.doi.org/10.1016/j.yexcr.2010.12.008, doi:10.1016/j.yexcr.2010.12.008. This article has 64 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.yexcr.2010.12.008)

[7. (Hua2020Enterohemorrhagic) Ying Hua, Jiali Wu, Muqing Fu, Jinyue Liu, Xiaoxia Li, Bao Zhang, Wei Zhao, and Chengsong Wan. Enterohemorrhagic escherichia coli effector protein espf interacts with host protein anxa6 and triggers myosin light chain kinase (mlck)-dependent tight junction dysregulation. Frontiers in Cell and Developmental Biology, December 2020. URL: http://dx.doi.org/10.3389/fcell.2020.613061, doi:10.3389/fcell.2020.613061. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fcell.2020.613061)

[8. (BandorowiczPikula2003A) Joanna Bandorowicz-Pikula, Aneta Kirilenko, Ruud van Deursen, Marcin Golczak, Michael Kühnel, Jean-Marc Lancelin, Slawomir Pikula, and René Buchet. A putative consensus sequence for the nucleotide-binding site of annexin a6. Biochemistry, 42(30):9137–9146, July 2003. URL: http://dx.doi.org/10.1021/bi034359m, doi:10.1021/bi034359m. This article has 20 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi034359m)

[9. (Enrich2011Annexin) Carlos Enrich, Carles Rentero, Sandra Vilà de Muga, Meritxell Reverter, Vishwaroop Mulay, Peta Wood, Meryem Koese, and Thomas Grewal. Annexin a6—linking ca2+ signaling with cholesterol transport. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1813(5):935–947, May 2011. URL: http://dx.doi.org/10.1016/j.bbamcr.2010.09.015, doi:10.1016/j.bbamcr.2010.09.015. This article has 71 citations.](https://doi.org/10.1016/j.bbamcr.2010.09.015)

[10. (Grewal2010Annexin) Thomas Grewal, Meryem Koese, Carles Rentero, and Carlos Enrich. Annexin a6-regulator of the egfr/ras signalling pathway and cholesterol homeostasis. The International Journal of Biochemistry & Cell Biology, 42(5):580–584, May 2010. URL: http://dx.doi.org/10.1016/j.biocel.2009.12.020, doi:10.1016/j.biocel.2009.12.020. This article has 59 citations.](https://doi.org/10.1016/j.biocel.2009.12.020)

[11. (AvilaSakar2000MembraneBound) Agustin J. Avila-Sakar, Robert H. Kretsinger, and Carl E. Creutz. Membrane-bound 3d structures reveal the intrinsic flexibility of annexin vi. Journal of Structural Biology, 130(1):54–62, May 2000. URL: http://dx.doi.org/10.1006/jsbi.2000.4246, doi:10.1006/jsbi.2000.4246. This article has 36 citations and is from a peer-reviewed journal.](https://doi.org/10.1006/jsbi.2000.4246)

[12. (Wu2021Analysis) WenBo Wu, GaoZhen Jia, Lei Chen, HaiTao Liu, and ShuJie Xia. Analysis of the expression and prognostic value of annexin family proteins in bladder cancer. Frontiers in Genetics, August 2021. URL: http://dx.doi.org/10.3389/fgene.2021.731625, doi:10.3389/fgene.2021.731625. This article has 12 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fgene.2021.731625)

[13. (Grewal2017Annexin) Thomas Grewal, Monira Hoque, James R. W. Conway, Meritxell Reverter, Mohamed Wahba, Syed S. Beevi, Paul Timpson, Carlos Enrich, and Carles Rentero. Annexin a6—a multifunctional scaffold in cell motility. Cell Adhesion & Migration, 11(3):288–304, January 2017. URL: http://dx.doi.org/10.1080/19336918.2016.1268318, doi:10.1080/19336918.2016.1268318. This article has 48 citations.](https://doi.org/10.1080/19336918.2016.1268318)