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Review
. 2014 Oct 15;3(4):981-93.
doi: 10.3390/cells3040981.

Regulation of TGF-β Superfamily Signaling by SMAD Mono-Ubiquitination

Feng Xie  1 , Zhengkui Zhang  1 , Hans van Dam  2 , Long Zhang  3 , Fangfang Zhou  4
Affiliations
Review

Regulation of TGF-β Superfamily Signaling by SMAD Mono-Ubiquitination

Feng Xie et al. Cells. .

Abstract

TGF-β(transforming growth factor-β) superfamily signaling mediators are important regulators of diverse physiological and pathological events. TGF-β signals are transduced by transmembrane type I and type II serine/threonine kinase receptors and their downstream effectors, the SMAD(drosophila mothers against decapentaplegic protein) proteins. Numerous studies have already demonstrated crucial regulatory roles for modification of TGF-β pathway components by poly-ubiquitination. Recently, several studies also uncovered mono-ubiquitination of SMADs as a mechanism for SMAD activation or inactivation. Mono-ubiquitination and subsequent deubiquitination of SMAD proteins accordingly play important roles in the control of TGF-β superfamily signaling. This review highlights the major pathways regulated by SMAD mono-ubiquitination.

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Figures

Figure 1
Figure 1
(A) Schematic representation of the ubiquitination procedure by E1, E2, and E3 enzymes; (B) Schematic representation of different ubiquitination patterns, including mono-ubiquitination, multi-ubiquitination, and poly-ubiquitination.
Figure 2
Figure 2
Schematic representation of TGF-β/SMAD and BMP/SMAD activation.
Figure 3
Figure 3
(A) SMURF2 and USP15 control the mono-ubiquitination state of SMAD3 (B) Mono-ubiquitination of SMAD3 by SMURF2 in the nucleus disrupts SMAD complexes.
Figure 4
Figure 4
Regulation of SMAD4 mono-ubiquitination by Ectodermin and FAM/USP9X.
Figure 5
Figure 5
(A) Proposed model for regulation of SMAD6 mono-ubiquitination by UBE2O and a hypothetical DUB; (B) Mono-ubiquitination of SMAD6 impairs its binding to the BMP type I receptor thereby elevating BMP/SMAD signaling.
See this image and copyright information in PMC

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