MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3

• DOI: 10.1038/s41388-021-02007-w
• Publication Date: 2021-09-13T03:14:37Z
• Authors: Sunil Kumar Singh; Sandeep Kumar; Navin Viswakarma; Daniel R. Principe; Subhasis Das; Gautam Sondarva; Rakesh Sathish Nair; Piush Srivastava; Subhash C. Sinha; Paul J. Grippo; Gregory R. J. Tha...; Basabi Rana; Ajay Rana
• Keywords: Lineage (genetic)

MAP4K4 is a Ste20 member and reported to play important roles in various pathologies, including cancer. However, the mechanism by which promotes pancreatic cancer not fully understood. It suggested that might function as promoter via specific downstream target(s) an organ-specific manner. Here we identified MLK3 direct target of MAP4K4. The associates with each other, phosphorylates on Thr738 increases kinase activity signaling. phosphorylation cell proliferation, migration, colony formation. Moreover, overexpressed human tumors directly correlates disease progression. MAP4K4-specific pharmacological inhibitor, GNE-495, impedes growth, induces death, arrests cycle Additionally, GNE-495 reduced tumor burden extended survival KPC mice inhibitor also protein expression, stroma, induced death murine tumors. These findings collectively suggest cancer, therefore therapies targeting alleviate patients.