Pik3ip1, also known as Phosphatidylinoinosidine-3-kinase interacting protein 1, is a unique transmembrane protein and a negative regulator of the Phosphoinositide 3-kinase (PI3K) pathway [1]. The PI3K pathway controls diverse cellular functions and is frequently dysregulated in cancer. Pik3ip1 binds directly to the p110 catalytic subunit of PI3K to negatively regulate its activity, and it plays a crucial role in various biological processes and disease conditions. Genetic models such as gene knockout (KO) mouse models are valuable for studying its functions.

In Pik3ip1-/-mice, enhanced T-cell responsiveness was observed upon immunization with a neoantigen, along with increased antitumor immunity and resistance to tumor growth, indicating that Pik3ip1 serves as a negative immune regulator that inhibits antitumor T-cell immunity [2]. In the experimental autoimmune encephalomyelitis (EAE) mouse model, down-regulation of Pik3ip1 in T cells led to a metabolic shift from oxidative phosphorylation to aerobic glycolysis, causing overactivation of T cells and aggressive disease progression [3]. In the context of cardiac hypertrophy, approximately 35% knockdown of Pik3ip1 in neonatal rat cardiomyocytes was sufficient to induce myocardial hypertrophy, while adenovirus-mediated overexpression of Pik3ip1 attenuated PI3K-mediated cardiac hypertrophy [4].

In conclusion, Pik3ip1 is an important negative regulator of the PI3K pathway. Model-based research, especially KO mouse models, has revealed its role in cancer, autoimmune diseases, and cardiac hypertrophy. These findings contribute to understanding the underlying mechanisms of these diseases and may provide potential molecular targets for treatment.

References:

1. Jia, Yingjie, He, Pengxing, Ma, Xubin, Liu, Ying, Xu, Yichao. 2024. PIK3IP1: structure, aberration, function, and regulation in diseases. In European journal of pharmacology, 977, 176753. doi:10.1016/j.ejphar.2024.176753. https://pubmed.ncbi.nlm.nih.gov/38897445/

2. Chen, Yichen, Wang, Jun, Wang, Xi, Cheng, Bin, Wang, Zhi. 2019. Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity. In Clinical cancer research : an official journal of the American Association for Cancer Research, 25, 6180-6194. doi:10.1158/1078-0432.CCR-18-4134. https://pubmed.ncbi.nlm.nih.gov/31350312/

3. Xie, Wenqiang, Fang, Juan, Shan, Zhongyan, Chen, Qianming, Wang, Zhi. 2022. Regulation of autoimmune disease progression by Pik3ip1 through metabolic reprogramming in T cells and therapeutic implications. In Science advances, 8, eabo4250. doi:10.1126/sciadv.abo4250. https://pubmed.ncbi.nlm.nih.gov/36179018/

4. Song, Hong Ki, Kim, Jiyeon, Lee, Jong Sub, Park, Woo Jin, Kim, Do Han. 2015. Pik3ip1 modulates cardiac hypertrophy by inhibiting PI3K pathway. In PloS one, 10, e0122251. doi:10.1371/journal.pone.0122251. https://pubmed.ncbi.nlm.nih.gov/25826393/