ANKRA2

ANKRA2 Full Name

ankyrin repeat, family A (RFXANK-like), 2

ANKRA2 Introduction

ANKRA2 (also known as ankyrin repeat-containing protein that interacts with the nuclear factor-kappa B activator 1, or ANKRA2) is a member of the ankyrin repeat family of adapter proteins that mediate protein-protein interactions. The gene encodes a scaffold protein containing multiple ankyrin repeats, which are 33-amino acid motifs that form helix-loop-helix structures and facilitate binding to various partner proteins. ANKRA2 was originally identified as an interactor of the NF-kappa B activator 1 (ACT1, also known as TRAF3IP2), linking it to inflammatory signaling pathways. It is also known as RFWD3-binding protein and has been implicated in the regulation of the ubiquitin-proteasome system through its interaction with E3 ubiquitin ligases. ANKRA2 is ubiquitously expressed in human tissues, with relatively higher levels detected in the heart, kidney, liver, and immune cells. Emerging evidence has implicated ANKRA2 in various biological processes including inflammation, cell cycle regulation, DNA damage response, and cancer progression, making it an increasingly recognized player in both normal physiology and disease pathogenesis.

Figure 1. Schematic structure of ANKRA2.

Biological Functions in Inflammation and NF-kappa B Signaling
ANKRA2 plays a significant role in the regulation of inflammatory responses through its interaction with ACT1 (NF-kappa B activator 1), an adaptor protein that links the IL-17 receptor to downstream signaling pathways. ANKRA2 binds directly to the C-terminal region of ACT1, forming a complex that modulates the activation of NF-kappa B and MAP kinase pathways. Upon IL-17 stimulation, the ANKRA2-ACT1 complex promotes the recruitment of TRAF6, leading to the activation of the IKK complex, subsequent I kappa B phosphorylation and degradation, and nuclear translocation of NF-kappa B. This results in the expression of pro-inflammatory cytokines including IL-6, IL-8, CXCL1, and CXCL2. ANKRA2 also negatively regulates NF-kappa B activation by promoting the ubiquitination and degradation of ACT1, providing a feedback mechanism to control inflammation. The balance between these opposing functions determines the duration and intensity of inflammatory responses. Beyond IL-17 signaling, ANKRA2 has been implicated in Toll-like receptor (TLR) signaling pathways. ANKRA2 interacts with TRAF6 and promotes its K63-linked polyubiquitination, which is essential for the activation of downstream kinases including TAK1 and IKK. Dysregulation of ANKRA2 expression or function has been associated with chronic inflammatory conditions including rheumatoid arthritis, inflammatory bowel disease, and psoriasis, where hyperactive NF-kappa B signaling drives tissue damage and disease progression.

Role in the Ubiquitin-Proteasome System and DNA Damage Response
ANKRA2 functions as an adapter protein that links substrate recognition to E3 ubiquitin ligase activity, thereby regulating protein stability and turnover. ANKRA2 directly interacts with RFWD3 (also known as RING finger and WD repeat domain 3), an E3 ubiquitin ligase involved in DNA damage response and cell cycle control. The ANKRA2-RFWD3 complex targets specific substrates for ubiquitination and subsequent proteasomal degradation, including histones and DNA repair factors. During the DNA damage response, ANKRA2 is recruited to sites of double-strand breaks, where it facilitates RFWD3-mediated ubiquitination of histone H2A and H2AX. This ubiquitination promotes the recruitment of downstream DNA repair proteins including BRCA1, 53BP1, and RAD51, thereby facilitating homologous recombination and non-homologous end joining. ANKRA2 also regulates the stability of p53 through its interaction with MDM2, an E3 ligase that targets p53 for degradation. ANKRA2 binds to MDM2 and promotes its autoubiquitination and degradation, leading to p53 stabilization and activation in response to genotoxic stress. This function links ANKRA2 to cell cycle arrest, apoptosis, and senescence. Furthermore, ANKRA2 regulates the stability of cyclin D1 and other cell cycle regulators, influencing G1/S phase transition. Consistent with these functions, ANKRA2 knockdown leads to genomic instability, impaired DNA repair, and increased sensitivity to DNA-damaging agents such as cisplatin and ionizing radiation.

Alternate Names for ANKRA2

ANKRA2; ankyrin repeat, family A (RFXANK-like), 2; ankyrin repeat family A protein 2; RFXANK-like protein 2; Ankra; AI450635; AU023827; 1110004M18Rik; MGC90650;