Nrarp, short for Notch-regulated ankyrin repeat protein, is a key molecule that serves as a molecular link between the Notch and Wnt signaling pathways [3,4,7]. It contains two ankyrin repeats and its gene is transcriptionally regulated by the Notch signaling pathway [6]. Nrarp plays significant roles in multiple biological processes, such as cell fate determination during embryogenesis, neural-crest-cell differentiation, and angiogenesis [4,5,7].

In T-cell acute lymphoblastic leukemia (T-ALL), Nrarp shows a dual role. Overexpression of Nrarp blocks NOTCH1 signaling and delays the proliferation of T-ALL cells with high Notch1 signaling, but promotes the expansion of T-ALL cells with lower Notch1 activity. It interacts with lymphoid enhancer-binding factor 1 (LEF1) and potentiates Wnt signaling in T-ALL cells with low Notch levels [2].

In breast cancer, downregulation of NRARP exerts anti-tumor activities depending on Wnt/β-catenin-mediated signals. miR-130a-3p can inhibit NRARP expression, leading to decreased cell proliferation, anchorage-independent growth, and migration of breast cancer cells [3].

In reninoma, structural variants generate canonical activating rearrangements of NOTCH1 while removing its negative regulator, NRARP. In single reninoma nuclei, excessive renin and NOTCH1 signalling mRNAs are observed, with non-excess NRARP expression [1].

In conclusion, Nrarp is a crucial regulator that coordinates Notch and Wnt signaling pathways, influencing various biological processes. Its dysregulation is associated with multiple diseases including T-ALL, breast cancer, and reninoma. Studies on Nrarp, especially through gene-knockout or conditional-knockout models, help to understand the molecular mechanisms underlying these diseases, potentially providing new therapeutic targets.