Abstract
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.
Highlights
Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4), known as HGK, is a serine/threonine kinase and belongs to the Ste20 family of kinases [1, 2]
The selection of pancreatic ductal adenocarcinoma (PDAC) cell lines was based on the relative expressions of both the MAP4K4 and MLK3 proteins (Supplementary Fig. 1b)
MAP4K4 was highly expressed in Capan-1 cells where MLK3 was present in substantial amounts (Supplementary Fig. 1b) and we determined the co-localization of these two proteins in Capan-1 cell line
Summary
Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4), known as HGK (hematopoietic progenitor kinase/ germinal center kinase-like kinase), is a serine/threonine kinase and belongs to the Ste family of kinases [1, 2]. Besides its indispensable function in embryonic development, MAP4K4 plays a central role in systemic inflammation [5], lung inflammation [6], focal adhesion dynamic [7], insulin sensitivity [8], atherosclerosis [4], immunity [9], and cancer [10,11,12,13]. It has been suggested that MAP4K4 could contribute to oncogenic transformation through regulating downstream targets [10]. MAP4K4 phosphorylates TRAF2 in T cells, promoting its degradation [14]; this has not been implicated in cancer. MAP4K4 directly phosphorylates a pleckstrin domain-containing protein FARP1 [15]; the implication of this phosphorylation in cancer is unknown. We sought to determine the MAP4K4-induced downstream signaling that can potentially promote oncogenic transformation
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