Review
Targeting of TAK1 in inflammatory disorders and cancer

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The transcription factors nuclear factor-κB (NF-κB) and activating protein-1 (AP-1) are critical regulators of stress responses, immunity, inflammation and cancer. A large variety of cellular stimuli utilize these signaling pathways through a common upstream kinase transforming growth factor-β-activated kinase 1 (TAK1). TAK1 was originally identified as a mitogen-activated kinase kinase kinase (MAP3K) activated by transforming growth factor-β (TGF-β); however, it has been characterized as a key regulator in inflammatory and immune signaling pathways. In addition, microbial proteins and components of host cell signaling scramble for the TAK1 complex in innate immunity. This review highlights the recent advances in the activation mechanisms and physiological functions of TAK1. Research targeting TAK1 raises the potential for new therapeutic options for inflammatory disorders, including cancer.

Section snippets

Update and impact on TAK1 signaling

The kinase TAK1 was discovered in 1995 by Matsumoto and colleagues in a complementation screen based on a MAPK pathway in yeast and characterized as a MAPK kinase kinase (MAP3K), which is activated by TGF-β and bone morphogenetic protein (BMP) [1]. However, during the decade after the original report, TAK1 was characterized and widely accepted as a key player in pro-inflammatory cytokine signaling, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and Toll-like receptor (TLR)

Emerging new functions of TAK1 in immunity

Both the NF-κB and AP-1 pathways play pivotal roles in the immune system. For example, deletion of genes encoding subunits of these transcription factors in lymphocytes and other immune cells causes several defects in the development of immune organs, including lymph nodes, and activation of acquired and innate immunity 38, 39. In addition, pharmacological interventions involving chemical inhibitors of protein kinases that regulate these transcription factors, including p38 and IKK, are

Microbial regulation of the TAK1 complex

Significant features of TAK1 in host defense are also illustrated by microbial targeting of the TAK1 complex (Figure 1). The Yersinia enterocolitica virulence factor YopP inhibits host cell NF-κB signaling by direct binding to TAB1 to synergistically potentiate the p38-mediated feedback regulation of TAK1 [57]. NleE, an enteropathogenic Escherichia coli that expresses the conserved bacterial type-III-secreted effector responsible for blocking host NF-κB signaling, interferes with the

Therapeutic intervention in inflammatory disorders

Protein kinases are promising molecular targets for therapeutic interventions. Several kinase inhibitors have been launched for the treatment of human diseases. In inflammatory signaling cascades, inhibitors of several protein kinases, including p38 and IKK, have been developed as candidates for inflammatory disorders such as rheumatoid arthritis and airway inflammation [66].

On the basis of its diverse functions, TAK1 has become one of the major target kinases in inflammatory disorders. Because

Targeting TAK1 in cancer therapy

In recent years it has become increasingly clear that the inflammatory and innate immune system plays a critical role in cancer development and progression. The tumor microenvironment is an established concept in which the relationship between chronic inflammation and cancer or the contribution of the stroma to tumor progression influences the development of pre-metastatic niches and the shaping of genetic signatures of metastatic cells. Deficiency of either Itch or CYLD, essential ubiquitin

Prospective strategies for targeting TAK1

As described above, systemic administration of selective chemical TAK1 inhibitors showed significant anti-inflammatory and anti tumor activities in animal models; however, the fact that TAK1 has diverse cellular functions increases the risk of adverse effects, especially susceptibility to bacterial and viral infections. It was recently reported that systemic TAK1–siRNA lipoplex delivery alleviates inflammation in experimental autoimmune arthritis with decreased frequency of Th1 and Th17 cells

Concluding remarks

As summarized in this review, TAK1 is now an attractive molecular target for the treatment of several human diseases; however, this possibility is mainly based on findings for cultured cells in vitro and loss-of-function studies in vivo. Information on where and when TAK1 is activated in injured tissues is completely lacking; therefore, establishment of immunohistochemistry for activated TAK1 will provide new information about its pathophysiological functions. Undesirable effects must also be

Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research on Innovative Areas and Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and grants from the Naito Memorial Foundation.

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