A Smurf1 tale: function and regulation of an ubiquitin ligase in multiple cellular networks
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Cellular and Molecular Life Sciences
REVIEW
A Smurf1 tale: function and regulation of an ubiquitin ligase in multiple cellular networks Yu Cao • Lingqiang Zhang
Received: 19 July 2012 / Revised: 5 September 2012 / Accepted: 11 September 2012 / Published online: 25 September 2012 Ó Springer Basel 2012
Abstract Since being discovered and intensively studied for over a decade, Smad ubiquitylation regulatory factor-1 (Smurf1) has been linked with several important biological pathways, including the bone morphogenetic protein pathway, the non-canonical Wnt pathway, and the mitogen-activated protein kinase pathway. Multiple functions of this ubiquitin ligase have been discovered in cell growth and morphogenesis, cell migration, cell polarity, and autophagy. Smurf1 is related to physiological manifestations in terms of age-dependent deficiency in bone formation and invasion of tumor cells. Smurf1-knockout mice have a significant phenotype in the skeletal system and considerable manifestations during embryonic development and neural outgrowth. In depth studying of Smurf1 will help us to understand the etiopathological mechanisms of related disorders. Here, we will summarize historical and recent studies on Smurf1, and discuss the E3 ligasedependent and -independent functions of Smurf1. Moreover, intracellular regulations of Smurf1 and related physiological phenotypes will be described in this review. Keywords Smurf1
Ubiquitylation E3 HECT domain
Y. Cao L. Zhang (&) State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China e-mail: [email protected] L. Zhang Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, Liaoning Province, China
Introduction There is a growing interest in the significant role ubiquitylation plays in benefiting or undermining regular biological processes. Ubiquitylation is believed to regulate the physiological and metabolic homeostasis of an organism, while abnormalities and deficiencies in this process are related to a broad range of diseases, including malignancies, neurodegenerative disorders, immune disorders, and inflammation [1, 2]. During ubiquitylation, one or more ubiquitins (Ub) are sequentially delivered though ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), and finally tagged onto the specific lysine residue of the targeted protein [3–5] (Fig. 1a). This tagged prey is then degraded by the proteasome or undergoes other biological processes such as changing its subcellular localization (Appendix 1). More than 600 E3s have been identified and they are mainly classified into RING (really interesting new gene) and HECT (homologous to E6AP C-terminus) types [6–8] (Appendix 2). Smad ubiquitylation regulatory factor-1 (Smurf1) has been identified as a HECT type E3, and, based on its structure, it belongs to the Nedd4 family. Having been studied for more than 10 years, Smurf1 has been related to multiple biological processes such as c
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