Casein kinase 2 promotes the TGF-β-induced activation of α-tubulin acetyltransferase 1 in fibroblasts cultured on a soft matrix
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Cell signals for growth factors depend on the mechanical propertiesof the extracellular matrix (ECM) surrounding the cells. Microtubule acetylation is involved in the transforming growthfactor (TGF)-β-induced myofibroblast differentiation in the softECM. However, the mechanism of activation of α-tubulin acetyltransferase1 (α-TAT1), a major α-tubulin acetyltransferase, inthe soft ECM is not well defined. Here, we found that caseinkinase 2 (CK2) is required for the TGF-β-induced activation ofα-TAT1 that promotes microtubule acetylation in the soft matrix. Genetic mutation and pharmacological inhibition of CK2catalytic activity specifically reduced microtubule acetylationin the cells cultured on a soft matrix rather than those culturedon a stiff matrix. Immunoprecipitation analysis showed that CK2α,a catalytic subunit of CK2, directly bound to the C-terminal domainof α-TAT1, and this interaction was more prominent inthe cells cultured on the soft matrix. Moreover, the substitutionof alanine with serine, the 236th amino acid located at theC-terminus, which contains the CK2-binding site of α-TAT1, significantlyabrogated the TGF-β-induced microtubule acetylationin the soft matrix, indicating that the successful binding of CK2and the C-terminus of α-TAT1 led to the phosphorylation ofserine at the 236th position of amino acids in α-TAT1 and regulationof its catalytic activity. Taken together, our findings providenovel insights into the molecular mechanisms underlyingthe TGF-β-induced activation of α-TAT1 in a soft matrix.
Abstract
Cell signals for growth factors depend on the mechanical propertiesof the extracellular matrix (ECM) surrounding the cells. Microtubule acetylation is involved in the transforming growthfactor (TGF)-β-induced myofibroblast differentiation in the softECM. However, the mechanism of activation of α-tubulin acetyltransferase1 (α-TAT1), a major α-tubulin acetyltransferase, inthe soft ECM is not well defined. Here, we found that caseinkinase 2 (CK2) is required for the TGF-β-induced activation ofα-TAT1 that promotes microtubule acetylation in the soft matrix. Genetic mutation and pharmacological inhibition of CK2catalytic activity specifically reduced microtubule acetylationin the cells cultured on a soft matrix rather than those culturedon a stiff matrix. Immunoprecipitation analysis showed that CK2α,a catalytic subunit of CK2, directly bound to the C-terminal domainof α-TAT1, and this interaction was more prominent inthe cells cultured on the soft matrix. Moreover, the substitutionof alanine with serine, the 236th amino acid located at theC-terminus, which contains the CK2-binding site of α-TAT1, significantlyabrogated the TGF-β-induced microtubule acetylationin the soft matrix, indicating that the successful binding of CK2and the C-terminus of α-TAT1 led to the phosphorylation ofserine at the 236th position of amino acids in α-TAT1 and regulationof its catalytic activity. Taken together, our findings providenovel insights into the molecular mechanisms underlyingthe TGF-β-induced activation of α-TAT1 in a soft matrix.
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