TGF-β-activated Kinase 1 (TAK1) and Apoptosis Signal-regulating Kinase 1 (ASK1) Interact with the Promyogenic Receptor Cdo to Promote Myogenic Differentiation via Activation of p38MAPK Pathway

Tran, Phong; Ho, Seok‐Man; Kim, Bok-Geon; Vuong, Tuan Anh; Leem, Young-Eun; Bae, Gyu‐Un; Kang, Jong‐Sun

doi:10.1074/jbc.m112.351601

Cited by 32 publications

(30 citation statements)

References 45 publications

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“…Next, we performed the gene-annotation enrichment analysis to find functional annotation clustering with the DAVID informatics tool (DAVID Bioinformatics Resources 6.8, National Institute of Allergy and Infectious Diseases/NIH) based on Gene Ontology (GO). Using the 446 differentially regulated genes, we identified nine biological GO terms such as "cell adhesion," "regulation of transferase activity," and "regulation of cell motion," consistent with the proposed role of Cdon (31)(32)(33) (Fig. 3 B and C and SI Appendix, Table 2).…”

Section: Cdon-deficient Hearts Exhibit Alterations In Gene Expressionsupporting

confidence: 59%

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

Jeong

Kim

Pyun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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On pathological stress, Wnt signaling is reactivated and induces genes associated with cardiac remodeling and fibrosis. We have previously shown that a cell surface receptor Cdon (cell-adhesion associated, oncogene regulated) suppresses Wnt signaling to promote neuronal differentiation however its role in heart is unknown. Here, we demonstrate a critical role of Cdon in cardiac function and remodeling. Cdon is expressed and predominantly localized at intercalated disk in both mouse and human hearts. Cdon-deficient mice develop cardiac dysfunction including reduced ejection fraction and ECG abnormalities.Cdon−/−hearts exhibit increased fibrosis and up-regulation of genes associated with cardiac remodeling and fibrosis. Electrical remodeling was demonstrated by up-regulation and mislocalization of the gap junction protein, Connexin 43 (Cx43) inCdon−/−hearts. In agreement with altered Cx43 expression, functional analysis both usingCdon−/−cardiomyocytes and shRNA-mediated knockdown in rat cardiomyocytes shows aberrant gap junction activities. Analysis of the underlying mechanism reveals thatCdon−/−hearts exhibit hyperactive Wnt signaling as evident by β-catenin accumulation and Axin2 up-regulation. On the other hand, the treatment of rat cardiomyocytes with a Wnt activator TWS119 reduces Cdon levels and aberrant Cx43 activities, similarly to Cdon-deficient cardiomyocytes, suggesting a negative feedback between Cdon and Wnt signaling. Finally, inhibition of Wnt/β-catenin signaling by XAV939, IWP2 or dickkopf (DKK)1 prevented Cdon depletion-induced up-regulation of collagen 1a and Cx43. Taken together, these results demonstrate that Cdon deficiency causes hyperactive Wnt signaling leading to aberrant intercellular coupling and cardiac fibrosis. Cdon exhibits great potential as a target for the treatment of cardiac fibrosis and cardiomyopathy.

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Section: Cdon-deficient Hearts Exhibit Alterations In Gene Expressionsupporting

confidence: 59%

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

Jeong

Kim

Pyun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…During myoblast differentiation, the cell surface receptor Cdo binds scaffold protein JLP and subsequently recruits MKK3/6 and p38MAPK (18,(35)(36)(37). In this Cdo-mediated p38MAPK activation, TAK1 and ASK1 function as MAP3Ks to promote myogenic differentiation (38). Besides phosphorylation, the spatial regulation of p38MAPK and its scaffold proteins is critical for performing their functions (39).…”

Section: Discussionmentioning

confidence: 99%

Hsp70 Interacts with Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 To Regulate p38MAPK Stability and Myoblast Differentiation during Skeletal Muscle Regeneration

Fan

Gao

Rao

et al. 2018

Molecular and Cellular Biology

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The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. In this study, we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38 mitogen-activated protein kinase α (p38MAPKα) but not AKT1 rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts. Moreover, Hsp70 interacted with MK2, a substrate of p38MAPK, to regulate the stability of p38MAPK. Knockdown of Hsp70 also led to downregulation of both MK2 and p38MAPK in intact muscles and during cardiotoxin-induced muscle regeneration. Hsp70 bound MK2 to regulate MK2-p38MAPK interaction in myoblasts. We subsequently identified the essential regions required for Hsp70-MK2 interaction. Functional analyses showed that MK2 is essential for both myoblast differentiation and skeletal muscle regeneration. Taken together, our findings reveal a novel role of Hsp70 in regulating myoblast differentiation by interacting with MK2 to stabilize p38MAPK.

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“…Immunoblot analysis was performed as previously described 30,31 . Briefly, the brain tissues were lysed in RIPA buffer (iNtRON Biotechnology, Korea) containing complete protease inhibitor cocktail (Roche), followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.…”

Section: Immunofluorescence Staining Immunoblotting and Rna Analysismentioning

confidence: 99%

PRMT7 deficiency causes dysregulation of the HCN channels in the CA1 pyramidal cells and impairment of social behaviors

Lee

Vuong

et al. 2020

Exp Mol Med

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HCN channels regulate excitability and rhythmicity in the hippocampal CA1 pyramidal cells. Perturbation in the HCN channel current (I h ) is associated with neuropsychiatric disorders, such as autism spectrum disorders. Recently, protein arginine methyltransferase 7 (PRMT7) was shown to be highly expressed in the hippocampus, including the CA1 region. However, the physiological function of PRMT7 in the CA1 neurons and the relationship to psychiatric disorders are unclear. Here we showed that PRMT7 knockout (KO) mice exhibit hyperactivity and deficits in social interaction. The firing frequency of the CA1 neurons in the PRMT7 KO mice was significantly higher than that in the wild-type (WT) mice. Compared with the WT CA1 neurons, the PRMT7 KO CA1 neurons showed a more hyperpolarized resting potential and a higher input resistance, which were occluded by the I h -current inhibitor ZD7288; these findings were consistent with the decreased I h and suggested the contribution of I h -channel dysfunction to the PRMT7 KO phenotypes. The HCN1 protein level was decreased in the CA1 region of the PRMT7 KO mice in conjunction with a decrease in the expression of Shank3, which encodes a core scaffolding protein for HCN channel proteins. A brief application of the PRMT7 inhibitor DS437 did not reproduce the phenotype of the PRMT7 KO neurons, further indicating that PRMT7 regulates I h by controlling the channel number rather than the open probability. Moreover, shRNA-mediated PRMT7 suppression reduced both the mRNA and protein levels of SHANK3, implying that PRMT7 deficiency might be responsible for the decrease in the HCN protein levels by altering Shank3 expression. These findings reveal a key role for PRMT7 in the regulation of HCN channel density in the CA1 pyramidal cells that may be amenable to pharmacological intervention for neuropsychiatric disorders.

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TGF-β-activated Kinase 1 (TAK1) and Apoptosis Signal-regulating Kinase 1 (ASK1) Interact with the Promyogenic Receptor Cdo to Promote Myogenic Differentiation via Activation of p38MAPK Pathway

Cited by 32 publications

References 45 publications

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

Hsp70 Interacts with Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 To Regulate p38MAPK Stability and Myoblast Differentiation during Skeletal Muscle Regeneration

PRMT7 deficiency causes dysregulation of the HCN channels in the CA1 pyramidal cells and impairment of social behaviors

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