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TAK1 MAPK kinase kinase mediates transforming growth factor-beta signaling by targeting SnoN oncoprotein for degradation.

ABSTRACT: Transforming growth factor-beta (TGF-beta) regulates a variety of physiologic processes through essential intracellular mediators Smads. The SnoN oncoprotein is an inhibitor of TGF-beta signaling. SnoN recruits transcriptional repressor complex to block Smad-dependent transcriptional activation of TGF-beta-responsive genes. Following TGF-beta stimulation, SnoN is rapidly degraded, thereby allowing the activation of TGF-beta target genes. Here, we report the role of TAK1 as a SnoN protein kinase. TAK1 interacted with and phosphorylated SnoN, and this phosphorylation regulated the stability of SnoN. Inactivation of TAK1 prevented TGF-beta-induced SnoN degradation and impaired induction of the TGF-beta-responsive genes. These data suggest that TAK1 modulates TGF-beta-dependent cellular responses by targeting SnoN for degradation.

SUBMITTER: Kajino T

PROVIDER: S-EPMC2175395 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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TAK1 MAPK kinase kinase mediates transforming growth factor-beta signaling by targeting SnoN oncoprotein for degradation.

Kajino Taisuke T Omori Emily E Ishii Shunsuke S Matsumoto Kunihiro K Ninomiya-Tsuji Jun J

The Journal of biological chemistry 20070202 13

Transforming growth factor-beta (TGF-beta) regulates a variety of physiologic processes through essential intracellular mediators Smads. The SnoN oncoprotein is an inhibitor of TGF-beta signaling. SnoN recruits transcriptional repressor complex to block Smad-dependent transcriptional activation of TGF-beta-responsive genes. Following TGF-beta stimulation, SnoN is rapidly degraded, thereby allowing the activation of TGF-beta target genes. Here, we report the role of TAK1 as a SnoN protein kinase. ...[more]

PMID: 17276978

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Project description:The origin of chronic pain is linked to inflammation, characterized by increased levels of proinflammatory cytokines in local tissues and systemic circulation. Transforming growth factor beta-activated kinase 1 (TAK1) is a key regulator of proinflammatory cytokine signaling that has been well characterized in the context of cancer and autoimmune disorders, yet its role in chronic pain is less clear. Here, we evaluated the ability of our TAK1 small-molecule inhibitor, takinib, to attenuate pain and inflammation in preclinical models of inflammatory, neuropathic, and primary pain. Inflammatory, neuropathic, and primary pain was modeled using intraplantar complete Freund's adjuvant (CFA), chronic constriction injury (CCI), and systemic delivery of the catechol-O-methyltransferase (COMT) inhibitor OR486, respectively. Behavioral responses evoked by mechanical and thermal stimuli were evaluated in separate groups of mice receiving takinib or vehicle prior to pain induction (baseline) and over 12 days following CFA injection, 4 weeks following CCI surgery, and 6 hours following OR486 delivery. Hindpaw edema was also measured prior to and 3 days following CFA injection. Upon termination of behavioral experiments, dorsal root ganglia (DRG) were collected to measure cytokines. We also evaluated the ability of takinib to modulate nociceptor activity via in vitro calcium imaging of neurons isolated from the DRG of Gcamp3 mice. In all 3 models, TAK1 inhibition significantly reduced hypersensitivity to mechanical and thermal stimuli and expression of proinflammatory cytokines in DRG. Furthermore, TAK1 inhibition significantly reduced the activity of tumor necrosis factor (TNF)-primed/capsaicin-evoked DRG nociceptive neurons. Overall, our results support the therapeutic potential of TAK1 as a novel drug target for the treatment of chronic pain syndromes with different etiologies. PERSPECTIVE: This article reports the therapeutic potential of TAK1 inhibitors for the treatment of chronic pain. This new treatment has the potential to provide a greater therapeutic offering to physicians and patients suffering from chronic pain as well as reduce the dependency on opioid-based pain treatments.

Dataset Information

TAK1 MAPK kinase kinase mediates transforming growth factor-beta signaling by targeting SnoN oncoprotein for degradation.

Publications

TAK1 MAPK kinase kinase mediates transforming growth factor-beta signaling by targeting SnoN oncoprotein for degradation.

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