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Roles for lysine residues of the MH2 domain of Smad3 in transforming growth factor‐β signaling
Author(s) -
Imoto Seiyu,
Sugiyama Kenji,
Sekine Yuichi,
Matsuda Tadashi
Publication year - 2005
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.04.023
Subject(s) - lysine , mutant , phosphorylation , transcription factor , microbiology and biotechnology , transforming growth factor beta , transforming growth factor , biology , signal transduction , mutation , transcriptional regulation , gene , biochemistry , amino acid
Sma and MAD‐related protein 3 (Smad3) plays a key role in the intracellular signaling of the transforming growth factor‐β (TGF‐β) family of growth factors, which exhibits a diverse set of cellular responses, including cell proliferation and differentiation. Smad3 has the N‐terminal Mad homology (MH) 1 and the C‐terminal MH2 domains. MH2 domain is essential for the TGF‐β‐induced transcriptional activation, because the MH2 domain of Smad3 is involved in the interactions with several transcriptional cofactors as well as the type I TGF‐β receptor (TβR‐I). In this study, we examined the roles for four lysine residues (Lys‐333, Lys‐341, Lys‐378, and Lys‐409) in the Smad3 MH2 domain. Mutation of the lysine (K)‐378 to arginine (R) (K378R) abolished the interaction with TβR‐I, phosphorylation, transcriptional activation by an active TβR‐I. The K341R mutant also failed to stimulate TGF‐β‐induced transcription by resting in the cytoplasm. However, the K409R mutant showed a higher transcriptional activity by stronger interactions with co‐activators, such as p300/CBP. Furthermore, both the K341R and K378R mutants act as dominant‐negative inhibitors in the TGF‐β‐induced target genes of endogenous TGF‐β signal. Thus, the lysine residues of Smad3 MH2 domain play important roles in the transcriptional regulation of TGF‐β signals through TβR‐I.