The molecular mechanisms associated with PIN7, a protein-protein interaction network of seven pleiotropic proteins.

PIN7 is a protein-protein interaction network of seven pleiotropic proteins (TPPII, CDK2, MYBBP1A, p53, SIRT6, SIRT7, and CD147) with proposed multiple functions in the aging and age-related diseases including cancer and neurodegeneration. Since the animal and cellular models with downregulated or knockout TPPII, p53, SIRT6, SIRT7, and MYBBP1A expression levels demonstrate similar age-related phenotype features, the interaction network was subjected to further investigation. For the identification of the main molecular mechanisms enabling the functions of the interaction network, PIN7 was subjected to the pathway enrichment, protein function prediction, and the protein node prioritization analysis using Cytoscape software and its applications GeneMania, ClusterOne, and Cyto-hubba. The study identified the p53 signaling pathway as the most dominant mediator of PIN7 effect. The top-ranked protein nodes of PIN7 extended by GeneMania application belong to the group of histone acetyltransferases and histone deacetylases. These enzymes are involved in the reverse epigenetic regulation mechanisms linked to the regulation of PTK2, NFκB, and p53 signaling interaction subnetworks of the extended PIN7. The analysis emphasized the role of PTK2 signaling, which functions upstream of the p53 signaling pathway, and its interaction network includes all top rank protein nodes of the extended PIN7 and all members of the sirtuin family (SIRT1-SIRT7). Further, the analysis suggests the involvement of molecular mechanisms related to metastatic cancer (prostate cancer, small cell lung cancer), hemostasis, the regulation of the thyroid hormones, and the cell cycle G1/S checkpoint. The additional data-mining analysis shows that the protein interaction network MYBBP1A-p53-TPPII-SIRT6-CD147 controls the Warburg effect, and MYBBP1A-p53-TPPII-SIRT7-CD147 influences mTOR signaling and autophagy. The proposed insights into the molecular mechanisms of aging and age-related diseases could be valuable for the discovery of new controlling interaction clusters, which could contribute to the development of the multitarget therapeutical strategies.