- Title
- ACTN4 regulates the stability of RIPK1 in melanoma
- Creator
- Zhang, Yuan Yuan; Tabataba, Hessam; Liu, Xiao Ying; Wang, Jia Yu; Yan, Xu Guang; Farrelly, Margaret; Jiang, Chen Chen; Guo, Su Tang; Liu, Tao; Kao, Hung-Ying; Thorne, Rick F.; Zhang, Xu Dong; Jin, Lei
- Relation
- NHMRC.1083496 http://purl.org/au-research/grants/nhmrc/1083496
- Relation
- Oncogene Vol. 37, p. 4033-4045
- Publisher Link
- http://dx.doi.org/10.1038/s41388-018-0260-x
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2018
- Description
- The actin crosslinking protein α-actinin-4 (ACTN4) is emerging as an important contributor to the pathogenesis of cancer. This has largely been attributed to its role in regulating cytoskeleton organization and its involvement in transcriptional regulation of gene expression. Here we report a novel function of ACTN4 as a scaffold necessary for stabilization of receptor-interacting protein kinase 1 (RIPK1) that we have recently found to be an oncogenic driver in melanoma. ACTN4 bound to RIPK1 and cellular inhibitor of apoptosis protein 1 (cIAP1) with its actin-binding domain at the N-terminus and the CaM-like domain at the C-terminus, respectively. This facilitated the physical association between RIPK1 and cIAP1 and was critical for stabilization of RIPK1 that in turn activated NF-κB. Functional investigations showed that silencing of ACTN4 suppressed melanoma cell proliferation and retarded melanoma xenograft growth. In contrast, overexpression of ACTN4 promoted melanocyte and melanoma cell proliferation and moreover, prompted melanocyte anchorage-independent growth. Of note, the expression of ACTN4 was transcriptionally activated by NF-κB. Taken together, our findings identify ACTN4 as an oncogenic regulator through driving a feedforward signaling axis of ACTN4-RIPK1-NF-κB, with potential implications for targeting ACTN4 in the treatment of melanoma.
- Subject
- cell signalling; melanoma; actin crosslinking protein α-actinin-4 (ACTN4); receptor-interacting protein kinase 1 (RIPK1); cellular inhibitor of apoptosis protein 1 (cIAP1); SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1419915
- Identifier
- uon:37515
- Identifier
- ISSN:0950-9232
- Rights
- This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1038/s41388-018-0260-x
- Language
- eng
- Full Text
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