The four and a half LIM-only protein 2 (FHL2) activates transforming growth factor beta (TGF-beta) signaling by regulating ubiquitination of the E3 ligase Arkadia

The four and a half LIM-only protein 2 (FHL2) activates transforming growth factor beta (TGF-beta) signaling by regulating ubiquitination of the E3 ligase Arkadia. Xia, T., Levy, L., Levillayer, F., Jia, B., Li, G., Neuveut, C., Buendia, M. A., Lan, K., & Wei, Y. J Biol Chem, 288(3):1785–94, January, 2013.
abstract bibtex

Arkadia is a RING-based ubiquitin ligase that positively regulates TGF-beta signaling by targeting several pathway components for ubiquitination and degradation. However, little is known about the mechanisms controlling Arkadia activity. Here we show that the LIM-only protein FHL2 binds and synergistically cooperates with Arkadia to activate Smad3/Smad4-dependent transcription. Knockdown of FHL2 by RNA interference decreases Arkadia level and restricts the amplitude of Arkadia-induced TGF-beta target gene responses. We found that Arkadia is ubiquitinated via K63- and K27-linked polyubiquitination. A single mutation at the RING domain that abolishes the E3 activity diminishes Arkadia ubiquitination, indicating that this modification partly involves autocatalytic process. Mutation of seven lysines at the C-terminal region of Arkadia severely impairs ubiquitination through the K27 but not the K63 linkage and slows down the turnover of Arkadia, suggesting that K27-linked polyubiquitination might promote proteolysis-dependent regulation of Arkadia. We show that FHL2 increases the half-life of Arkadia through inhibition of ubiquitin chain assembly on the protein, which provides a molecular basis for functional cooperation between Arkadia and FHL2 in enhancing TGF-beta signaling. Our study uncovers a novel regulatory mechanism of Arkadia by ubiquitination and identifies FHL2 as important regulator of Arkadia ubiquitination and TGF-beta signal transduction.

@article{xia_four_2013,
	title = {The four and a half {LIM}-only protein 2 ({FHL2}) activates transforming growth factor beta ({TGF}-beta) signaling by regulating ubiquitination of the {E3} ligase {Arkadia}},
	volume = {288},
	issn = {1083-351X (ELECTRONIC); 0021-9258 (LINKING)},
	shorttitle = {The four and a half {LIM}-only protein 2 ({FHL2}) activates transforming growth factor beta ({TGF}-beta) signaling by regulating ubiquitination of the {E3} ligase {Arkadia}},
	abstract = {Arkadia is a RING-based ubiquitin ligase that positively regulates TGF-beta signaling by targeting several pathway components for ubiquitination and degradation. However, little is known about the mechanisms controlling Arkadia activity. Here we show that the LIM-only protein FHL2 binds and synergistically cooperates with Arkadia to activate Smad3/Smad4-dependent transcription. Knockdown of FHL2 by RNA interference decreases Arkadia level and restricts the amplitude of Arkadia-induced TGF-beta target gene responses. We found that Arkadia is ubiquitinated via K63- and K27-linked polyubiquitination. A single mutation at the RING domain that abolishes the E3 activity diminishes Arkadia ubiquitination, indicating that this modification partly involves autocatalytic process. Mutation of seven lysines at the C-terminal region of Arkadia severely impairs ubiquitination through the K27 but not the K63 linkage and slows down the turnover of Arkadia, suggesting that K27-linked polyubiquitination might promote proteolysis-dependent regulation of Arkadia. We show that FHL2 increases the half-life of Arkadia through inhibition of ubiquitin chain assembly on the protein, which provides a molecular basis for functional cooperation between Arkadia and FHL2 in enhancing TGF-beta signaling. Our study uncovers a novel regulatory mechanism of Arkadia by ubiquitination and identifies FHL2 as important regulator of Arkadia ubiquitination and TGF-beta signal transduction.},
	number = {3},
	journal = {J Biol Chem},
	author = {Xia, T. and Levy, L. and Levillayer, F. and Jia, B. and Li, G. and Neuveut, C. and Buendia, M. A. and Lan, K. and Wei, Y.},
	month = jan,
	year = {2013},
	keywords = {Animals Binding Sites Cell Line, Reporter Half-Life Humans LIM-Homeodomain Proteins/ genetics/metabolism Luciferases Mice Muscle Proteins/ genetics/metabolism Mutation Nuclear Proteins/ genetics/metabolism Protein Binding Protein Structure, Tertiary Signal Transduction Transcription Factors/ genetics/metabolism Transfection Transforming Growth Factor beta/ genetics/metabolism Ubiquitin/ genetics/metabolism Ubiquitin-Protein Ligases/ genetics/metabolism Ubiquitination, Tumor Fibroblasts/cytology/metabolism Gene Expression Regulation Genes},
	pages = {1785--94},
}

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