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

TitleMAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3.
Publication TypeJournal Article
Year of Publication2021
AuthorsSingh SKumar, Kumar S, Viswakarma N, Principe DR, Das S, Sondarva G, Nair RSathish, Srivastava P, Sinha SC, Grippo PJ, Thatcher GRJ, Rana B, Rana A
Date Published2021 10
KeywordsAnimals, Cell Line, Tumor, Cell Movement, Cell Proliferation, Disease Progression, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase Kinases, Mice, Neoplasm Transplantation, Pancreatic Neoplasms, Phosphorylation, Protein Serine-Threonine Kinases, Threonine, Up-Regulation

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

Alternate JournalOncogene
PubMed ID34511598
PubMed Central IDPMC8553609
Grant ListIK6 BX004855 / BX / BLRD VA / United States
F30 CA236031 / CA / NCI NIH HHS / United States
R01 CA178063 / CA / NCI NIH HHS / United States
R01 CA216410 / CA / NCI NIH HHS / United States
R03 CA219764 / CA / NCI NIH HHS / United States
I01 BX004903 / BX / BLRD VA / United States
I01 BX003296 / BX / BLRD VA / United States
R01 CA176846 / CA / NCI NIH HHS / United States