Abstract 1677: The emerging role of the Plasminogen-Apple-Nematode (PAN) domain in cancer therapy

Abstract The Plasminogen-Apple-Nematode (PAN) domain, with a core of four to six cysteine residues, is found in more than 28,000 proteins across 959 genera. However, its role in protein function still needs to be elucidated. Numerous proteins initially characterized the PAN domain, including a well-known master regulator for cancer cell proliferation, HGF (Hepatocyte growth factor). Abnormal regulation of HGF-mediated signaling results in multiple deadly cancers. The binding of HGF to its cell surface receptor, c-MET, triggers signaling pathways, which leads to cancer. Here, we show that mutating four core cysteine residues in the HGF PAN domain reduces c-MET interaction, subsequent c-MET autophosphorylation, and phosphorylation of its downstream targets, perinuclear localization, cellular internalization of HGF and its receptor, c-MET, and c-MET ubiquitination. Furthermore, transcriptional activation of HGF/c-MET signaling-related genes involved in cancer progression, invasion, metastasis, and cell survival was impaired. Thus, targeting the PAN domain of HGF may represent a mechanism for selectively regulating the binding and activation of the c-MET pathway. Additionally, we found this domain in the tumor suppressor gene, MST1 (macrophage stimulating 1), and mutating the domain altered the protein function through protein stability and ubiquitination. In another study, we show that cysteine residues in the vestigial plasminogen-apple-nematode (PAN) domain of NRP1 are necessary for SARS-CoV-2 spike protein internalization. Mutating novel cysteine residues in the PAN altered NRP1 stability and downstream activation of the extracellular signal-regulated kinase (ERK) signaling pathway, impairing its interaction with the spike protein. These results show the diverse critical role of the PAN domain beyond cancer therapy. Citation Format: Kuntal De, Debjani Pal, Wellington Muchero. The emerging role of the Plasminogen-Apple-Nematode (PAN) domain in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1677.