Map4k4 Signaling Nodes in Metabolic and Cardiovascular Diseases

Abstract

Map4k4, originally identified in siRNA screens and characterized by tissue specific gene deletions, is emerging as a regulator of glucose homeostasis and cardiovascular health. Recent studies have shown that Map4k4 gene ablation or inhibition of its kinase activity attenuates hyperglycemia and plaque formation in mouse models of insulin resistance and atherosclerosis, and suggest roles for Map4k4 in multiple signaling systems, including NFκB activation, small GTPase regulation, the Hippo cascade, and regulation of cell dynamics by FERM domain proteins. This new and promising area of inquiry raises key questions that need to be addressed in the future, such as defining which of the above or other effectors mediate Map4k4 control of metabolic and vascular functions, and identifying upstream activators of Map4k4.

MAP4K4: an emerging therapeutic target in cancer

“…Besides its essential role in embryonic development, MAP4K4 has also been implicated in focal adhesion dynamics regulation [13], systemic inflammation [14], lung inflammation [15], type 2 diabetes [16, 17], atherosclerosis [18] and insulin sensitivity [19]. For detailed information regarding MAP4K4 in immunity/inflammation and metabolic/cardiovascular diseases, we refer the reader to two excellent reviews [20, 21]. In this review, we will discuss current understanding of MAP4K4 regulation and summarize evidence that implicates MAP4K4 in cancer.…”

“…In addition to above mentioned candidate downstream mediators of MAP4K4, MAP4K4 also participated in the regulation of other cancer-related signaling pathways or factors including insulin pathway, hippo signaling (LATS1/2 and YAP/TAZ) and mTOR/AMPK [19, 21, 43, 47–52]. Although experimental evidence that supports the link between MAP4K4 and these pathways and cancer is currently not available, it is reasonable to believe that MAP4K4 could contribute to cancer through modulating these pathways or factors in a context-dependent manner.…”

Molecular docking performance evaluated on the D3R Grand Challenge 2015 drug-like ligand datasets

“…The D3R Grand Challenge 2015 was focused on two protein targets ( Figure 1): Heat Shock Protein 90 (HSP90) [1][2][3][4][5][6][7][8][9][10][11][12] and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) [13][14][15][16][17][18][19][20][21][22]. In Phase 1 the participants were asked to provide affinity predictions for 180 HSP90 ligands and pose prediction for 6 of them, as well as pose prediction for 30 MAP4K4 ligands and affinity predictions for 18 of them.…”

N‐acetyl‐seryl‐aspartyl‐lysyl‐proline is a valuable endogenous antifibrotic peptide for kidney fibrosis in diabetes: An update and translational aspects

“…Mitogen‐activated protein kinase kinase kinase kinase 4 (MAP4K4), a member of the Sterile 20 family of kinases, has various biological roles. In endothelial cells, MAP4K4 has been shown to suppress integrin β1 activity by inducing moesin.…”