Cytokines play important roles in human development and disease. Specificity and cross-talk of cytokine signaling pathways appear to be important for fine-tuning stress responses and cell fate decision during development. Transforming growth factor beta (TGF-beta) is involved in cell growth, differentiation, tissue remodeling, immune response and angiogenesis. Interleukin 1 (IL-1) pathway plays a central role in the generation of inflammatory responses. We have found that both TGF-beta and IL-1 activate TGF-beta activated kinase 1 (TAK1) MAPKKK. Active form of TAK1 can enhance both TGF-beta- and IL-l-dependent transcription. In response to IL-1 stimulation, TAK1 activates transcription factors AP-1 and NF-KappaB. While TGF-6 stimulation does activate TAK1, the role of TAK1 in TGF-beta signaling pathway is not known. Recently, we found that TAK1 associates with a transcriptional repressor SnoN, a negative regulator of TGF-beta signaling. TAK1 induces degradation of SnoN. We hypothesize that TGF-beta activates TAK1 to induce phosphorylation of SnoN and targets SnoN for proteasomal degradation, thereby up-regulating TGF-b signal transduction. In addition, we hypothesize that TGF-beta and IL-1 activate TAK1 in distinct manner via specific scaffold/regulatory proteins to induce their unique cellular responses. Thus, the overall objectives of this proposal are; to delineate the pathway and functional role of TAK1 in TGF-beta signaling and to elucidate the mechanisms through which TAK1 regulates signal pathway specificity. To accomplish these objectives and to test our hypotheses we will: i) determine the mechanism and role of TAK1-induced SnoN degradation in TGF-b signaling pathway; ii) isolate and characterize molecules associated with TAK1 and iii) generate a skin specific knockout of TAK1 to characterize the in vivo role of TAK1 in a tissue in which TGF-beta play important roles. These studies will address unsolved questions regarding the mechanisms of TGF-beta and IL-1 family signaling and will provide an understanding of the physiological function of TAK 1 in vivo.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Marino, Pamela
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North Carolina State University Raleigh
Public Health & Prev Medicine
Schools of Earth Sciences/Natur
United States
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Liu, Xia; Hayano, Satoru; Pan, Haichun et al. (2018) Compound mutations in Bmpr1a and Tak1 synergize facial deformities via increased cell death. Genesis 56:e23093
Sakamachi, Yosuke; Morioka, Sho; Mihaly, September R et al. (2017) TAK1 regulates resident macrophages by protecting lysosomal integrity. Cell Death Dis 8:e2598
Mihaly, September R; Sakamachi, Yosuke; Ninomiya-Tsuji, Jun et al. (2017) Noncanocial cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGF?-activated kinase 1. Sci Rep 7:2918
Sai, Kazuhito; Morioka, Sho; Takaesu, Giichi et al. (2016) TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus. J Cell Sci 129:1855-65
Morioka, S; Sai, K; Omori, E et al. (2016) TAK1 regulates hepatic lipid homeostasis through SREBP. Oncogene 35:3829-38
Simmons, A N; Kajino-Sakamoto, R; Ninomiya-Tsuji, J (2016) TAK1 regulates Paneth cell integrity partly through blocking necroptosis. Cell Death Dis 7:e2196
Hashimoto, Kazunori; Simmons, Alicia N; Kajino-Sakamoto, Rie et al. (2016) TAK1 Regulates the Nrf2 Antioxidant System Through Modulating p62/SQSTM1. Antioxid Redox Signal 25:953-964
Lane, Jamie; Yumoto, Kenji; Azhar, Mohamad et al. (2015) Tak1, Smad4 and Trim33 redundantly mediate TGF-?3 signaling during palate development. Dev Biol 398:231-41
Mihaly, S R; Ninomiya-Tsuji, J; Morioka, S (2014) TAK1 control of cell death. Cell Death Differ 21:1667-76
Mihaly, September R; Morioka, Sho; Ninomiya-Tsuji, Jun et al. (2014) Activated macrophage survival is coordinated by TAK1 binding proteins. PLoS One 9:e94982

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