Research progress of ankyrin repeat domain 1 protein: an updated review

Abstract

Ankyrin repeat domain 1 (Ankrd1) is an acute response protein that belongs to the muscle ankyrin repeat protein (MARP) family. Accumulating evidence has revealed that Ankrd1 plays a crucial role in a wide range of biological processes and diseases. This review consolidates current knowledge on Ankrd1's functions in myocardium and skeletal muscle development, neurogenesis, cancer, bone formation, angiogenesis, wound healing, fibrosis, apoptosis, inflammation, and infection. The comprehensive profile of Ankrd1 in cardiovascular diseases, myopathy, and its potential as a candidate prognostic and diagnostic biomarker are also discussed. In the future, more studies of Ankrd1 are warranted to clarify its role in diseases and assess its potential as a therapeutic target.

Keywords: Angiogenesis; Ankrd1; Cardiovascular diseases; Skeletal muscle diseases; Tumor therapy.

Fig. 1

Schematic representation of Ankrd1 structure and molecular regulation of Ankrd1 at different levels. At the transcriptional level, p38, Rac1, and transcription factors Nkx2.5 and GATA-4 bind to the Ankrd1 promoter and positively regulates Ankrd1 expression. The miR-92a-3p can translocate into the nucleus and positively mediate Ankrd1 expression by AGO2. At the posttranscriptional level, miR-3614-5p binds to the 3′UTR of the Ankrd1 gene and decrease Ankrd1 expression. The RNA-binding protein RBMS1 can also bind to the 3′ untranslated region (UTR) and increase the mRNA stabilization of Ankrd1. The Ankrd1 protein has 319 amino acids, including one coiled-coil domain, two PEST-like regions, two putative nuclear localization signals (NLSs), five tandem ankyrin repeats (ANK), and one potential nuclear export signal (NES). At the posttranslational level, Ankrd1 can be phosphorylated by PKCα and ROCK1. Calpain 3 can cleavage by Ankrd1 protein at the first NLS. This diagram is not drawn to scale

Fig. 2

The cellular roles of Ankrd1 in cardiomyocytes. As a transcriptional regulator, Ankrd1 participates in the regulation of transcriptional activity by interacting with different transcriptional factors (TFs), including YB-1, GATA 4, and p53. The biological functions in cells regulated by Ankrd1 and these TFs are displayed in gray boxes. Ankrd1 is also a structural protein, and contributes to the structural integrity of the sarcomere by interacting with titin, CASQ2, and myopalladin. This figure was improved on the basis of the study by Samaras SE et al. [27]

Fig. 3

Genetic studies have identified several Ankrd1 mutations in CHD, HCM and DCM. The middle part of the figure is a schematic representation of human Ankrd1 structure. The upper part of the figure shows the specific location of mutations in protein. The lower part of the figure shows the interaction protein of Ankrd1 with known specific binding sites. This figure was improved on the basis of the study by Ling SSM et al. [2]

Fig. 4

Ankrd1 participates in tumor progression. Ankrd1 inhibits apoptosis by Bcl2 and GADD153. Ankrd1 promotes stemness and proliferation of breast cancer stem cells. Ankrd1 enhances drug resistance, such as cisplatin, phenylbutyrate, afatinib, and osimertinib. Ankrd1 promotes tumor migration and invasiveness by inhibiting apoptosis in colorectal cancer cell lines. Ankrd1 activates the pro-tumorigenic properties of cancer-associated fibroblasts via AP-1 complex

Fig. 5

Ankrd1 plays important roles in wound healing, nerves, and virus infection. The green text box shows the effects after knock-down or knock-out Ankrd1 expression, the yellow text box represents the performance after Ankrd1 overexpression