Pcdh1, short for protocadherin-1, is a member of the cadherin superfamily and plays a role in cell-cell adhesion. It has been associated with multiple biological pathways and diseases.

In the context of airway-related biology, it is linked to asthma-associated pathways, interacting with SMAD3 to regulate TGF-β1-induced gene transcription in bronchial epithelial cells [7]. It is also identified as a susceptibility gene for bronchial hyperresponsiveness, suggesting its importance in maintaining the integrity of the airway epithelium [8].

In pancreatic ductal adenocarcinoma (PDAC), Pcdh1 expression is upregulated, associated with tumor invasion and lymph node metastasis. High Pcdh1 levels predict poor overall survival. Mechanistically, Pcdh1 enhances p65 nuclear localization by interacting with KPNB1, activating the NF-κB signaling pathway [1]. In another study on pancreatic adenocarcinoma, Pcdh1 was found to promote cancer cell metastasis, and its RNA levels were significantly down-regulated by flutamide treatment [2].

Regarding hantavirus infection, Pcdh1 is essential for the entry of New World hantaviruses (Andes virus and Sin Nombre virus) into pulmonary endothelial cells. Genetic ablation of Pcdh1 in Syrian golden hamsters renders them highly resistant to a usually lethal Andes virus challenge [3]. Also, two point mutations in Pcdh1 can disrupt hantavirus recognition and protect Syrian hamsters from pulmonary disease and death caused by Andes virus [4].

In IgA vasculitis (IgAV), serum and urinary concentrations of Pcdh1 are significantly higher in patients compared to the control group, suggesting its potential involvement in the pathogenesis of IgAV [5]. In early childhood, common variations in Pcdh1 increase the risk of developing both transient early asthma and atopic dermatitis [6].

In summary, Pcdh1 is crucial in cell-cell adhesion and is involved in multiple disease-related processes. Its role in promoting PDAC progression, enabling hantavirus entry, and contributing to the pathogenesis of IgAV, asthma, and atopic dermatitis has been revealed through various in vivo and genetic studies. The genetic ablation and mutation studies in animal models, especially in hamsters for hantavirus-related research, have provided valuable insights into its functions in these disease conditions.

References:

1. Ye, Zhihua, Yang, Yingyu, Wei, Ying, Wang, Xinyi, Zhang, Junkai. 2022. PCDH1 promotes progression of pancreatic ductal adenocarcinoma via activation of NF-κB signalling by interacting with KPNB1. In Cell death & disease, 13, 633. doi:10.1038/s41419-022-05087-y. https://pubmed.ncbi.nlm.nih.gov/35864095/

2. Du, Xingyi, Yi, Xiaoyu, Zou, Xiaocui, Ren, Xuhong, He, Xinhua. 2023. PCDH1, a poor prognostic biomarker and potential target for pancreatic adenocarcinoma metastatic therapy. In BMC cancer, 23, 1102. doi:10.1186/s12885-023-11474-1. https://pubmed.ncbi.nlm.nih.gov/37957639/

3. Jangra, Rohit K, Herbert, Andrew S, Li, Rong, Dye, John M, Chandran, Kartik. 2018. Protocadherin-1 is essential for cell entry by New World hantaviruses. In Nature, 563, 559-563. doi:10.1038/s41586-018-0702-1. https://pubmed.ncbi.nlm.nih.gov/30464266/

4. Slough, Megan M, Li, Rong, Herbert, Andrew S, Wang, Zhongde, Chandran, Kartik. 2023. Two point mutations in protocadherin-1 disrupt hantavirus recognition and afford protection against lethal infection. In Nature communications, 14, 4454. doi:10.1038/s41467-023-40126-y. https://pubmed.ncbi.nlm.nih.gov/37488123/

5. Held, Martina, Kozmar, Ana, Sestan, Mario, Frkovic, Marijan, Jelusic, Marija. 2024. Insight into the Interplay of Gd-IgA1, HMGB1, RAGE and PCDH1 in IgA Vasculitis (IgAV). In International journal of molecular sciences, 25, . doi:10.3390/ijms25084383. https://pubmed.ncbi.nlm.nih.gov/38673968/

6. Mortensen, Li J, Kreiner-Møller, Eskil, Hakonarson, Hakon, Bønnelykke, Klaus, Bisgaard, Hans. 2013. The PCDH1 gene and asthma in early childhood. In The European respiratory journal, 43, 792-800. doi:10.1183/09031936.00021613. https://pubmed.ncbi.nlm.nih.gov/23988763/

7. Faura Tellez, Grissel, Vandepoele, Karl, Brouwer, Uilke, Koppelman, Gerard H, Nawijn, Martijn C. 2015. Protocadherin-1 binds to SMAD3 and suppresses TGF-β1-induced gene transcription. In American journal of physiology. Lung cellular and molecular physiology, 309, L725-35. doi:10.1152/ajplung.00346.2014. https://pubmed.ncbi.nlm.nih.gov/26209277/

8. Koppelman, Gerard H, Meyers, Deborah A, Howard, Timothy D, Bleecker, Eugene R, Postma, Dirkje S. 2009. Identification of PCDH1 as a novel susceptibility gene for bronchial hyperresponsiveness. In American journal of respiratory and critical care medicine, 180, 929-35. doi:10.1164/rccm.200810-1621OC. https://pubmed.ncbi.nlm.nih.gov/19729670/