TGF-β-activated Kinase 1 (Tak1) Mediates Agonist-induced Smad Activation and Linker Region Phosphorylation in Embryonic Craniofacial Neural Crest-derived Cells

Yumoto, Kenji; Thomas, Penny S.; Lane, Jamie; Matsuzaki, K; Inagaki, Manabu; Ninomiya‐Tsuji, Jun; Scott, Gregory J.; Ray, Manas K.; Ishii, Masahiko; Maxson, Robert E.; Mishina, Yuji; Kaartinen, Vesa

doi:10.1074/jbc.m112.431775

Cited by 71 publications

(62 citation statements)

References 46 publications

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“…23 These two signaling routes, however, are not completely separate, as interactions between TAK1 and the Smad proteins have been described. 24,25 In catabolic conditions ( + OAS-CM), we found effects of inhibition of TAK1. Improvement of chondrogenesis by the inhibition of TAK1 was found in these conditions.…”

Section: Discussionmentioning

confidence: 67%

Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Osteoarthritis-Like Conditions

Beuningen

Melle

Vitters

et al. 2014

Tissue Engineering Part A

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Objective: To rescue chondrogenic differentiation of human mesenchymal stem cells (hMSCs) in osteoarthritic conditions by inhibition of protein kinases. Methods: hMSCs were cultured in pellets. During early chondrogenic differentiation, these were exposed to osteoarthritic synovium-conditioned medium (OAS-CM), combined with the Janus kinase ( JAK)-inhibitor tofacitinib and/or the transforming growth factor b-activated kinase 1 (TAK1)-inhibitor oxozeaenol. To evaluate effects on chondrogenesis, the glycosaminoglycan (GAG) content of the pellets was measured at the time that chondrogenesis was manifest in control cultures. Moreover, mRNA levels of matrix molecules and enzymes were measured during this process, using real-time polymerase chain reaction (RT-PCR). Initial experiments were performed with hMSCs from a fetal donor, and results of these studies were confirmed with hMSCs from adult donors. Results: Exposure to OAS-CM resulted in pellets with a much lower GAG content, reflecting inhibited chondrogenic differentiation. This was accompanied by decreased mRNA levels of aggrecan, type II collagen, and Sox9, and increased levels of matrix metalloproteinase (MMP)1, MMP3, MMP13, ADAMTS4, and ADAMTS5. Both tofacitinib ( JAK-inhibitor) and oxozeaenol (TAK1 inhibitor) significantly increased the GAG content of the pellets in osteoarthritis (OA)-like conditions. The combination of both protein kinase inhibitors showed an additive effect on GAG content. In agreement with this, in the presence of OAS-CM, both tofacitinib and oxozeaenol increased mRNA expression of sox9. The expression of aggrecan and type II collagen was also up-regulated, but this only reached significance for aggrecan after TAK1 inhibition. Both inhibitors decreased the mRNA levels of MMP1, 3, and 13 in the presence of OAS-CM. Moreover, oxozeaenol also significantly down-regulated the mRNA levels of aggrecanases ADAMTS4 and ADAMTS5. When combined, the inhibitors caused additive reduction of OA-induced MMP1 mRNA expression. Counteraction of OAS-CM-induced inhibition of chondrogenesis by these protein kinase inhibitors was confirmed with hMSCs of two different adult donors. Both tofacitinib and oxozeaenol significantly improved GAG content in cell pellets from these adult donors. Conclusions: Tofacitinib and oxozeaenol partially prevent the inhibition of chondrogenesis by factors secreted by OA synovium. Their effects are additive. This indicates that these protein kinase inhibitors can potentially be used to improve cartilage formation under the conditions occurring in osteoathritic, or otherwise inflamed, joints.

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Section: Discussionmentioning

confidence: 67%

Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Osteoarthritis-Like Conditions

Beuningen

Melle

Vitters

et al. 2014

Tissue Engineering Part A

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“…The in vivo role of TAK1 as a mediator of BMP signaling is also supported by silencing the expression of this kinase in chondrocytes, where differentiation is impaired (Shim et al 2009), and in the germline causing vascular defects similar to the knockout of Smad5 (Jadrich et al 2006). Interestingly, neural crest -specific inactivation of TAK1 expression caused overall craniofacial hypoplasia, including cleft palate, and in addition to the defective p38 MAP kinase signaling downstream of TGF-b and BMP, these animals also showed defective R-Smad phosphorylation, especially at their linker region, suggesting a central role of TAK1 as a coordinator of both MAP kinase and Smad functions in vivo (Yumoto et al 2013).…”

Section: Signaling Via Smad and Non-smad Pathwaysmentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

544

498

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Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3 0 -kinase, and Rho GTPases.

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“…Imbalance may occur between signaling through nonSmad and Smad pathways during fibro-carcinogenesis. In particular, JNK activated by TGF-b induces expression of sphingosine kinase 1 in a Smad-independent manner [31,43].…”

Section: Introductionmentioning

confidence: 99%

“…The linker domain undergoes regulatory phosphorylation by mitogen-activated protein kinase (MAPK) pathways including extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK), p38 MAPK, and cyclin-dependent kinase (CDK) as well as glycogen synthase kinase 3-b (Fig. 1a, middle) [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37].…”

Section: Introductionmentioning

confidence: 99%

TGF-β signal shifting between tumor suppression and fibro-carcinogenesis in human chronic liver diseases

2013

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TGF-β-activated Kinase 1 (Tak1) Mediates Agonist-induced Smad Activation and Linker Region Phosphorylation in Embryonic Craniofacial Neural Crest-derived Cells

Cited by 71 publications

References 46 publications

Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Osteoarthritis-Like Conditions

Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Stem Cells in Osteoarthritis-Like Conditions

Signaling Receptors for TGF-β Family Members

TGF-β signal shifting between tumor suppression and fibro-carcinogenesis in human chronic liver diseases

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