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Regulatory role of E3 ubiquitin ligase Smurf2 on transcriptional corepressor KAP1

ABSTRACT: An E3 ubiquitin ligase Smurf2 and transcriptional co-repressor KAP1 have been documented to play crucial roles in similar cellular pathways including cell cycle, DNA damage response, chromatin compaction, senescence and cell death. Smurf2 and KAP1, through regulation of these cellular processes either drive or suppress tumorigenesis. Studies till date confer Smurf2 with a dual role in carcinogenesis, an oncogene and a tumor suppressor, depending on the cellular context. However, the molecular mechanisms governing Smurf2 functions remain unclear. Furthermore, studies have demonstrated significantly altered KAP1 protein levels in many human malignancies, despite which, the mechanisms operating in and regulating KAP1 stability and activity are obscure. In this study, we obtained evidence which indicates a strong and dynamic association between Smurf2 and KAP1. We found that Smurf2 directly binds KAP1 through its C2, WW1 and HECT domains. Further mechanistic studies also revealed that Smurf2 multi(mono)ubiquitinates KAP1 in E3 ligase-dependent manner. Moreover, Smurf2 differentially alters KAP1 protein levels in different types of mammalian and cancer cells and tissues, and significantly alters KAP1 interactome. Based on these findings, we propose a mechanism to explain the dual role and differential regulation of Smurf2 on KAP1 in a cell-context dependent manner. Further investigations of the identified Smurf2/KAP1 module could potentially lead to development of new, more efficient diagnostics tools and treatment paradigms.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: [Pooja Shah

LAB HEAD: Michael Blank

PROVIDER: PXD029642 | Pride | 2022-04-07

REPOSITORIES: Pride

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