Inpp4b, also known as inositol polyphosphate 4-phosphatase type II, is a key regulator primarily known for its role in negatively regulating the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway [1]. In response to growth factor stimulation, class I PI3K generates PtdIns(3,4,5)P3, which can be hydrolysed by inositol polyphosphate 5-phosphatases to PtdIns(3,4)P2. Both PtdIns(3,4,5)P3 and PtdIns(3,4)P2 facilitate AKT activation for cell processes like proliferation, survival, migration, and metabolism. Inpp4b hydrolyses PtdIns(3,4)P2, thus negatively regulating PI3K/AKT signalling. It has been implicated in cancer development, metabolic syndrome, and other disorders, making it an important gene for understanding various biological processes and diseases [1,3].

In Inpp4b-/-male mice, there is reduced energy expenditure and respiratory exchange ratio, leading to increased adiposity and insulin resistance. When fed a high-fat diet, these mice develop type II diabetes, adipose tissue and prostate inflammation, and high-grade prostatic intraepithelial neoplasia (PIN). This indicates that Inpp4B plays a crucial role in maintaining overall metabolic health and protecting from prostate neoplasms associated with metabolic dysfunction [3]. In HER2+ breast cancer, overexpression of Inpp4B inhibits cell proliferation, migration, and growth of xenografts, while its depletion promotes epithelial-mesenchymal transition (EMT) progression through activating the PDK1/AKT and Wnt/β-catenin signalling pathways [2]. In glioma, Inpp4B overexpression restrains cell proliferation, migration, apoptosis resistance, PD-L1 expression, and T cell suppression by glioma cells, suggesting it may inhibit glioma progression and immune escape [4]. In gastric cancer, Inpp4B may play dual roles as an oncogene and tumour suppressor gene in different tissue grades and clinical stages. Its overexpression enhances the phosphorylation of SGK3 in AGS cells, while its knockdown enhances the p-Akt level in BGC823 cells [5].

In conclusion, Inpp4b is a significant regulator of the PI3K/AKT signalling pathway, influencing various biological processes. The use of Inpp4b-/-mouse models has revealed its importance in metabolic health and protection from prostate neoplasms related to metabolic dysfunction. In cancer, its role varies depending on the cancer type and context, highlighting its complexity and the need for further research to fully understand its functions and implications for disease treatment.

References:

1. Hamila, Sabryn A, Ooms, Lisa M, Rodgers, Samuel J, Mitchell, Christina A. 2021. The INPP4B paradox: Like PTEN, but different. In Advances in biological regulation, 82, 100817. doi:10.1016/j.jbior.2021.100817. https://pubmed.ncbi.nlm.nih.gov/34216856/

2. Qu, Na, Wang, Gang, Su, Yue, Peng, Yang, Zhou, Weiying. 2024. INPP4B suppresses HER2-induced mesenchymal transition in HER2+ breast cancer and enhances sensitivity to Lapatinib. In Biochemical pharmacology, 226, 116347. doi:10.1016/j.bcp.2024.116347. https://pubmed.ncbi.nlm.nih.gov/38852646/

3. Zhang, Manqi, Ceyhan, Yasemin, Kaftanovskaya, Elena M, Ittmann, Michael M, Agoulnik, Irina U. 2021. INPP4B protects from metabolic syndrome and associated disorders. In Communications biology, 4, 416. doi:10.1038/s42003-021-01940-6. https://pubmed.ncbi.nlm.nih.gov/33772116/

4. Sun, Xiaoming, Chen, Yani, Tao, Xiaoyang, Ruan, Zhihua, Chen, Zhuo. 2022. INPP4B inhibits glioma cell proliferation and immune escape via inhibition of the PI3K/AKT signaling pathway. In Frontiers in oncology, 12, 983537. doi:10.3389/fonc.2022.983537. https://pubmed.ncbi.nlm.nih.gov/36147923/

5. Wu, Youliang, Wang, Xiaodong, Lu, Yida, Sun, Yanjun, Li, Yongxiang. 2021. INPP4B exerts a dual role in gastric cancer progression and prognosis. In Journal of Cancer, 12, 7201-7213. doi:10.7150/jca.58397. https://pubmed.ncbi.nlm.nih.gov/34729121/