Pin1, also known as peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, is a unique cis-trans peptidyl prolyl isomerase. It specifically binds to and catalyzes cis-trans conformational changes of specific Ser/Thr-Pro motifs after phosphorylation [2,4,5,6,7,8]. This activity plays a pivotal role in regulating the structure and function of its protein substrates, and is involved in multiple signaling pathways such as Raf/MEK/ERK, PI3K/Akt, Wnt/β-catenin, NF-κB [3]. Pin1 is of great biological importance as it impacts various cellular processes and is associated with diseases like cancer and neurodegenerative disorders [1,2,3,4,5,7,8]. Genetic models, like KO/CKO mouse models, are valuable tools for studying its functions.

Pin1-/-mice exhibit developmental bone defects and reduced mineralization. Pin1 targets RUNX2, SMAD1/5, and β-catenin in the FGF, BMP, and WNT pathways respectively, and has multiple roles in the crosstalk between different anabolic bone signaling pathways, controlling osteoblastogenesis and osteoclastogenesis [9]. In Alzheimer's disease, dysfunction or loss-of-function of Pin1 is an important step in pathogenesis [1]. In cancer, Pin1 overexpression is highly correlated with malignancy. It promotes cancer progression by increasing the stabilities of oncoproteins and decreasing those of tumor suppressors, and is involved in metabolic reprogramming like the Warburg effect [2,3,4,5,8].

In conclusion, Pin1 is crucial for normal cellular function, especially in processes related to bone cell differentiation, neurodegeneration, and cancer development. Studies using Pin1 KO/CKO mouse models have revealed its key roles in these biological processes and disease conditions, highlighting its potential as a therapeutic target for bone diseases, Alzheimer's disease, and cancer [1,3,8,9].

References:

1. Malter, James S. 2022. Pin1 and Alzheimer's disease. In Translational research : the journal of laboratory and clinical medicine, 254, 24-33. doi:10.1016/j.trsl.2022.09.003. https://pubmed.ncbi.nlm.nih.gov/36162703/

2. Jeong, Jessica, Usman, Muhammad, Li, Yitong, Zhou, Xiao Zhen, Lu, Kun Ping. 2024. Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation. In Cells, 13, . doi:10.3390/cells13090731. https://pubmed.ncbi.nlm.nih.gov/38727267/

3. Wu, Wenda, Xue, Xuezhen, Chen, Yan, Zheng, Ning, Wang, Jichuang. 2022. Targeting prolyl isomerase Pin1 as a promising strategy to overcome resistance to cancer therapies. In Pharmacological research, 184, 106456. doi:10.1016/j.phrs.2022.106456. https://pubmed.ncbi.nlm.nih.gov/36116709/

4. Caligiuri, Isabella, Vincenzo, Canzonieri, Asano, Tomochiro, Kumar, Vinit, Rizzolio, Flavio. 2023. The metabolic crosstalk between PIN1 and the tumour microenvironment. In Seminars in cancer biology, 91, 143-157. doi:10.1016/j.semcancer.2023.03.001. https://pubmed.ncbi.nlm.nih.gov/36871635/

5. Nakatsu, Yusuke, Yamamotoya, Takeshi, Ueda, Koji, Matsubara, Akio, Asano, Tomoichiro. 2019. Prolyl isomerase Pin1 in metabolic reprogramming of cancer cells. In Cancer letters, 470, 106-114. doi:10.1016/j.canlet.2019.10.043. https://pubmed.ncbi.nlm.nih.gov/31678165/

6. Born, Alexandra, Henen, Morkos A, Vögeli, Beat. 2019. Activity and Affinity of Pin1 Variants. In Molecules (Basel, Switzerland), 25, . doi:10.3390/molecules25010036. https://pubmed.ncbi.nlm.nih.gov/31861908/

7. Lu, Kun Ping, Zhou, Xiao Zhen. 2024. Pin1-catalyzed conformational regulation after phosphorylation: A distinct checkpoint in cell signaling and drug discovery. In Science signaling, 17, eadi8743. doi:10.1126/scisignal.adi8743. https://pubmed.ncbi.nlm.nih.gov/38889227/

8. Wang, Nan, Chai, Tian, Wang, Xing-Rong, Sang, Chun-Yan, Yang, Jun-Li. 2024. Pin1: Advances in pancreatic cancer therapeutic potential and inhibitors research. In Bioorganic chemistry, 153, 107869. doi:10.1016/j.bioorg.2024.107869. https://pubmed.ncbi.nlm.nih.gov/39418844/

9. Islam, Rabia, Yoon, Won-Joon, Ryoo, Hyun-Mo. 2017. Pin1, the Master Orchestrator of Bone Cell Differentiation. In Journal of cellular physiology, 232, 2339-2347. doi:10.1002/jcp.25442. https://pubmed.ncbi.nlm.nih.gov/27225727/