Nfatc2ip, also known as NIP45, is an evolutionarily conserved protein. It is crucial for SUMO-dependent genome integrity, collaborating with the SMC5/6 complex. It contains tandem SUMO-like domains and may play a role in post-replicative resolution of replication or recombination intermediates [1]. It is also involved in pathways related to breast cancer metastasis, cardiac hypertrophy, inflammatory responses, and muscle growth, and is associated with weight-loss in response to diet interventions [2-6, 10].

In SUMOylation inhibition studies, cells lacking Nfatc2ip are viable but hypersensitive to SUMO E1 inhibition, with the accumulation of mitotic chromosome bridges and micronuclei [1]. In breast cancer, TRPV6 promotes metastasis by increasing Nfatc2ip phosphorylation, which activates NFATC2 and upregulates ADAMTS6 expression [2]. miR-31-5p targets Nfatc2ip to inhibit myocardial hypertrophy, and Nfatc2ip binds to the core-promoter of β-Mhc to enhance its transcriptional activity [3]. In rainbow trout, miR-301b-5p and Nfatc2ip regulate inflammatory responses under high-temperature stress [4]. Porcine TRPC1 promotes muscle growth by facilitating the accumulation of intracellular Ca2+ and nuclear translocation of the NFATC2/NFATC2IP complex [5].

In conclusion, Nfatc2ip has diverse essential functions in maintaining genome integrity, cancer metastasis, cardiac hypertrophy, inflammatory regulation, and muscle growth. Studies using gene-knockout or other loss-of-function models have revealed its role in these biological processes and related disease conditions, providing insights into potential therapeutic targets for breast cancer, heart diseases, and understanding the response of organisms to environmental stress and muscle development.