Smurf E3 ubiquitin ligases at the cross roads of oncogenesis and tumor suppression |
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Authors: | Diana David S. Asha Nair M. Radhakrishna Pillai |
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Affiliation: | Cancer research Program, Rajiv Gandhi Centre for Biotechnology, Trivandrum-695 014, Kerala, India |
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Abstract: | Smad ubiquitin regulatory factors (Smurfs) belong to the HECT- family of E3 ubiquitin ligases and comprise mainly of two members, Smurf1 and Smurf2. Initially, Smurfs have been implicated in determining the competence of cells to respond to TGF-β/BMP signaling pathway. Nevertheless, the intrinsic catalytic activity has extended the repertoire of Smurf substrates beyond the TGF-β/BMP super family expanding its realm further to epigenetic modifications of histones governing the chromatin landscape. Through regulation of a large number of proteins in multiple cellular compartments, Smurfs regulate diverse cellular processes, including cell-cycle progression, cell proliferation, differentiation, DNA damage response, maintenance of genomic stability, and metastasis. As the genomic ablation of Smurfs leads to global changes in histone modifications and predisposition to a wide spectrum of tumors, Smurfs are also considered to have a novel tumor suppressor function. This review focuses on regulation network and biological functions of Smurfs in connection with its role in cancer progression. By providing a portrait of their protein targets, we intend to link the substrate specificity of Smurfs with their contribution to tumorigenesis. Since the regulation and biological functions of Smurfs are quite complex, understanding the oncogenic potential of these E3 ubiquitin ligases may facilitate the development of mechanism-based drugs in cancer treatment. |
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Keywords: | UPS, ubiquitin&ndash proteasome system HECT, homologous to E6-AP carboxyl terminus Smurfs, Smad ubiquitin regulatory factors TGF-β, transforming growth factor-beta NES, nuclear export signal sequence BMP, bone morphogenetic protein R-Smads, receptor regulated Smads I-Smads, inhibitory Smads Mad2, mitotic arrest deficient 2 NEDD9, neural precursor cell expressed, developmentally down-regulated 9 HEF1, human enhancer of filamentation 1 ING2, inhibitor of growth TRAF, TNF receptor associated factor JNK, c-Jun N-terminal Kinase HMECs, human mammary epithelial cells CKIP-1, casein kinase-2 interacting protein-1 |
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