The p53-Reprimo-Hippo-YAP-p73 pathway: An extrinsic apoptosis mechanism for tumor suppression

The p53 tumor suppressor gene is the most commonly mutated gene in human cancer and plays a central role in tumor suppression. We have identified and characterized the molecular function of several novel p53 target genes, including Noxa , AEN , FUCA1 , IER5 , and PHLDA3 (Science, 2000; Cell, 2009; PNAS, 2014, etc). RPRM is a p53 target gene implicated in tumor suppression; however, its molecular function has remained largely elusive. Here we report that Reprimo, the protein product of RPRM , is secreted and extrinsically induces apoptosis in recipient cells (PNAS, 2025). We further identified FAT1, FAT4, CELSR1, CELSR2, and CELSR3, members of the protocadherin family, as cell-surface receptors for Reprimo. Subsequent analyses revealed that upon binding to these receptors, Reprimo activates the Hippo-YAP-p73 axis, leading to apoptosis through transactivation of pro-apoptotic p73 target genes. In addition, we demonstrate that Reprimo converts YAP signaling from a tumor-promoting to a tumor-suppressive program by inhibiting the expression of YAP-driven oncogenic genes. In vivo analyses further support the tumor-suppressive effects of secreted Reprimo. Collectively, these findings identify the p53-Reprimo-Hippo-YAP-p73 pathway as a novel extrinsic apoptosis mechanism essential for tumor suppression. The discovery of Reprimo as an innate tumor eliminator and its downstream signaling pathway provides a promising new avenue for the pharmacological treatment of cancer.