TGF-β activated kinase 1 (TAK1) is a mediator of various cytokine signaling pathways. Germline deficiency of Tak1 causes multiple abnormalities, including dilated blood vessels at midgestation. However, the mechanisms by which TAK1 regulates vessel formation have not been elucidated. TAK1 binding proteins 1 and 2 (TAB1 and TAB2) are activators of TAK1, but their roles in embryonic TAK1 signalin...

Macrophages play diverse roles in tissue homeostasis and immunity, and canonically activated macrophages are critically associated with acute inflammatory responses. It is known that activated macrophages undergo cell death after transient activation in some settings, and the viability of macrophages impacts on inflammatory status. Here we report that TGFβ- activated kinase (TAK1) activators, T...

Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor (GPCR) for thrombin and promotes inflammatory responses through multiple pathways including p38 mitogen-activated protein kinase signaling. The mechanisms that govern PAR1-induced p38 activation remain unclear. Here, we define an atypical ubiquitin-dependent pathway for p38 activation used by PAR1 that regulates endothelial ba...

The liver is the first line of defense from environmental stressors in that hepatocytes respond to and metabolize them. Hence, hepatocytes can be damaged by stressors. Protection against hepatic cell damage and cell death is important for liver function and homeostasis. TAK1 (MAP3K7) is an intermediate of stressors such as bacterial moieties-induced signal transduction pathways in several cell ...

TNFα and IL-1β are two proinflammatory cytokines that play critical roles in many diseases, including rheumatoid arthritis and infectious diseases. How TNFα- and IL-1β-mediated signaling is finely tuned is not fully elucidated. Here, we identify tripartite-motif protein 38 (TRIM38) as a critical negative regulator of TNFα- and IL-1β-triggered signaling. Overexpression of TRIM38 inhibited activa...

TAB2 and TAB3 activate the Jun N-terminal kinase and nuclear factor-kappaB pathways through the specific recognition of Lys 63-linked polyubiquitin chains by its Npl4 zinc-finger (NZF) domain. Here we report crystal structures of the TAB2 and TAB3 NZF domains in complex with Lys 63-linked diubiquitin at 1.18 and 1.40 A resolutions, respectively. Both NZF domains bind to the distal ubiquitin thr...

Congenital heart defects (CHDs) are the most common major developmental anomalies and the most frequent cause for perinatal mortality, but their etiology remains often obscure. We identified a locus for CHDs on 6q24-q25. Genotype-phenotype correlations in 12 patients carrying a chromosomal deletion on 6q delineated a critical 850 kb region on 6q25.1 harboring five genes. Bioinformatics prioriti...

A cytokine/stress signaling kinase Tak1 (Map3k7) deficiency is known to impair hematopoietic progenitor cells. However, the role of TAK1 signaling in the stem cell function of the hematopoietic system is not yet well defined. Here we characterized hematopoietic stem cells (HSCs) harboring deletion of Tak1 and its activators, Tak1 binding proteins 1 and 2 (Tab1 and Tab2) using a competitive tran...

Advanced-stage breast cancers frequently metastasize to the bones and cause bone destruction, but the underlying mechanism is not fully understood. This study presents evidence that TGF-b–activated protein kinase 1 (TAK1) signaling in tumor cells promotes bone destruction by metastatic breast carcinoma cells, controlling expression of prometastatic factors including matrix metalloproteinase (MM...

Fruit flies have effective immune response against Gram-negative bacteria. Upon infection, early JNK-signaling pathway mediated response is followed by the action of the Immune deficiency (Imd) signaling cascade, a Drosophila equivalent of mammalian TNF-receptor pathway, leading to the release of antimicrobial peptides. Recently, Tak1-binding protein 2 (Tab2) and Inhibitor of apoptosis 2 (Iap2)...