Ppp6c encodes the catalytic subunit of protein phosphatase 6 (PP6), a serine/threonine phosphatase. PP6 is involved in multiple cellular processes such as cell growth, DNA repair, and immune responses, and is associated with pathways like the cGAS-STING pathway, NF-κB signaling, and the RAF-MEK-ERK cascade [3,4,5]. Genetic models, especially gene knockout mouse models, have been crucial in studying its functions.

In melanoma, Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis. Ppp6c heterozygous tumors show increased cell division and faster growth. Also, knockdown of Ppp6c in the heterozygous line promotes genomic damage and apoptosis [1]. In tongue carcinogenesis, Ppp6c deficiency accelerates K-rasG12D-induced tumor development, enhancing the activation of multiple signaling axes and DNA double-strand break accumulation [2]. In innate immune responses, PPP6C depletion enhances certain DNA/RNA-induced innate immune responses by negatively regulating STING phosphorylation [3]. In necroptosis, PPP6C deficiency protects cells from TNF-induced necroptosis through activation of TAK1 [4].

In conclusion, Ppp6c is a key regulator in various biological processes. Gene knockout mouse models have revealed its significance in cancer development, innate immunity, and necroptosis. These findings contribute to understanding the underlying mechanisms of related diseases and may provide potential therapeutic targets.

References:

1. Kanazawa, Kosuke, Kishimoto, Kazuhiro, Nomura, Miyuki, Tanuma, Nobuhiro, Shima, Hiroshi. 2021. Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis. In Cancer science, 112, 2233-2244. doi:10.1111/cas.14895. https://pubmed.ncbi.nlm.nih.gov/33743547/

2. Kishimoto, Kazuhiro, Kanazawa, Kosuke, Nomura, Miyuki, Tsuji, Hiroyuki, Shima, Hiroshi. 2021. Ppp6c deficiency accelerates K-rasG12D -induced tongue carcinogenesis. In Cancer medicine, 10, 4451-4464. doi:10.1002/cam4.3962. https://pubmed.ncbi.nlm.nih.gov/34145991/

3. Ni, Guoxin, Ma, Zhe, Wong, Jason P, Major, M Ben, Damania, Blossom. 2020. PPP6C Negatively Regulates STING-Dependent Innate Immune Responses. In mBio, 11, . doi:10.1128/mBio.01728-20. https://pubmed.ncbi.nlm.nih.gov/32753499/

4. Zou, Yonggang, Zheng, Qi, Jiang, Bin, Wu, Ming, Song, Hai. 2022. Deficiency of PPP6C protects TNF-induced necroptosis through activation of TAK1. In Cell death & disease, 13, 618. doi:10.1038/s41419-022-05076-1. https://pubmed.ncbi.nlm.nih.gov/35842423/

5. Cho, Eunice, Lou, Hua Jane, Kuruvilla, Leena, Calderwood, David A, Turk, Benjamin E. . PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK. In Cell reports, 34, 108928. doi:10.1016/j.celrep.2021.108928. https://pubmed.ncbi.nlm.nih.gov/33789117/