ACTN4 regulates the stability of RIPK1 in melanoma

Yuan Yuan Zhang, Hessam Tabataba, Xiao Ying Liu, Jia Yu Wang, Xu Guang Yan, Margaret Farrelly, Chen Chen Jiang, Su Tang Guo, Tao Liu, Hung-Ying Kao, Rick F. Thorne, Xu Dong Zhang, Lei Jin

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4033-4045
Number of pages13
JournalOncogene
Volume37
Issue number29
DOIs
Publication statusPublished - 2018 Jul 19

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Receptor-Interacting Protein Serine-Threonine Kinases
Actinin
Protein Kinases
Melanoma
Inhibitor of Apoptosis Proteins
Melanocytes
Actins
Cell Proliferation
Gene Expression Regulation
Growth
Cytoskeleton
Heterografts

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Zhang, Y. Y., Tabataba, H., Liu, X. Y., Wang, J. Y., Yan, X. G., Farrelly, M., ... Jin, L. (2018). ACTN4 regulates the stability of RIPK1 in melanoma. Oncogene, 37(29), 4033-4045. https://doi.org/10.1038/s41388-018-0260-x
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. / ACTN4 regulates the stability of RIPK1 in melanoma. In: Oncogene. 2018 ; Vol. 37, No. 29. pp. 4033-4045.
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abstract = "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.",
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Zhang, YY, Tabataba, H, Liu, XY, Wang, JY, Yan, XG, Farrelly, M, Jiang, CC, Guo, ST, Liu, T, Kao, H-Y, Thorne, RF, Zhang, XD & Jin, L 2018, 'ACTN4 regulates the stability of RIPK1 in melanoma', Oncogene, vol. 37, no. 29, pp. 4033-4045. https://doi.org/10.1038/s41388-018-0260-x

ACTN4 regulates the stability of RIPK1 in melanoma. / 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.

In: Oncogene, Vol. 37, No. 29, 19.07.2018, p. 4033-4045.

Research output: Contribution to journalArticle

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T1 - ACTN4 regulates the stability of RIPK1 in melanoma

AU - Zhang, Yuan Yuan

AU - Tabataba, Hessam

AU - Liu, Xiao Ying

AU - Wang, Jia Yu

AU - Yan, Xu Guang

AU - Farrelly, Margaret

AU - Jiang, Chen Chen

AU - Guo, Su Tang

AU - Liu, Tao

AU - Kao, Hung-Ying

AU - Thorne, Rick F.

AU - Zhang, Xu Dong

AU - Jin, Lei

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Y1 - 2018/7/19

N2 - 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.

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Zhang YY, Tabataba H, Liu XY, Wang JY, Yan XG, Farrelly M et al. ACTN4 regulates the stability of RIPK1 in melanoma. Oncogene. 2018 Jul 19;37(29):4033-4045. https://doi.org/10.1038/s41388-018-0260-x