Pdk1, also known as 3-phosphoinositide-dependent protein kinase 1, is a master kinase regulating AGC kinase family members such as AKT, SGK, PLK, S6K and RSK [1]. It is a key transducer of PI3K signaling, coordinating signals from extracellular cues to the cytoskeletal machinery for cell movement [4]. Pdk1 is involved in numerous biological processes including cell growth, metastasis, invasion, apoptosis, and survival time, making it biologically significant [1]. Mouse models are valuable for studying Pdk1's functions [1].

In a genetic mouse model, Smurf1 deficiency, which affects the Smurf1-mediated PDK1 neddylation in the PI3K-Akt signaling pathway, dramatically reduces colorectal cancer tumorigenesis, indicating PDK1's role in tumorigenesis [2]. In breast cancer, PDK1 knockdown reduced the proliferation, migration, and tumorigenicity of breast cancer cells and inhibited the HIF-1α pathway, showing its promoting effect on breast cancer progression [3]. Also, downregulation of PDK1 levels inhibits migration and experimental metastasis of human breast cancer cells, suggesting its role in cancer cell dissemination [5].

In conclusion, Pdk1 is a crucial regulator in multiple biological processes and is closely associated with cancer development, including colorectal and breast cancer. Findings from gene-knockout (KO) or conditional-knockout (CKO) mouse models have revealed its promoting role in tumorigenesis and cancer cell metastasis, highlighting its potential as a therapeutic target in cancer treatment.

References:

1. Zheng, Nana, Wei, Jiaqi, Wu, Depei, Xu, Yang, Guo, Jianping. 2023. Master kinase PDK1 in tumorigenesis. In Biochimica et biophysica acta. Reviews on cancer, 1878, 188971. doi:10.1016/j.bbcan.2023.188971. https://pubmed.ncbi.nlm.nih.gov/37640147/

2. Peng, Zhiqiang, Fang, Wei, Wu, Bo, Cui, Chun-Ping, Zhang, Lingqiang. 2024. Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer. In Nature chemical biology, 21, 59-70. doi:10.1038/s41589-024-01683-5. https://pubmed.ncbi.nlm.nih.gov/39039255/

3. Wei, Yu, Zhang, Dian, Shi, He, Guo, Bianqin, Chen, Tingmei. 2023. PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α. In Genes & diseases, 11, 101041. doi:10.1016/j.gendis.2023.06.013. https://pubmed.ncbi.nlm.nih.gov/38560503/

4. Gagliardi, Paolo Armando, di Blasio, Laura, Primo, Luca. 2015. PDK1: A signaling hub for cell migration and tumor invasion. In Biochimica et biophysica acta, 1856, 178-88. doi:10.1016/j.bbcan.2015.07.003. https://pubmed.ncbi.nlm.nih.gov/26238471/

5. Raimondi, C, Falasca, M. . Targeting PDK1 in cancer. In Current medicinal chemistry, 18, 2763-9. doi:. https://pubmed.ncbi.nlm.nih.gov/21568903/