Abstract
The receptor-interacting protein kinase 4 (RIPK4) plays an important role in the development and maintenance of various tissues including skin, but its role in melanoma has not been reported. Using patient-derived cell lines and clinical samples, we show that RIPK4 is expressed in melanomas at different levels. This heterogenous expression, together with very low level of RIPK4 in melanocytes, indicates that the role of this kinase in melanoma is context-dependent. While the analysis of microarray data has revealed no straightforward correlation between the stage of melanoma progression and RIPK4 expression in vivo, relatively high levels of RIPK4 are in metastatic melanoma cell lines. RIPK4 down-regulation by siRNA resulted in the attenuation of invasive potential as assessed by time-lapse video microscopy, wound-healing and transmigration assays. These effects were accompanied by reduced level of pro-invasive proteins such as MMP9, MMP2, and N-cadherin. Incubation of melanoma cells with phorbol ester (PMA) increased PKC-1β level and hyperphosphorylation of RIPK4 resulting in degradation of RIPK4. Interestingly, incubation of cells with PMA for short and long durations revealed that cell migration is controlled by the NF-κB signaling in a RIPK4-dependent (RIPK4high) or independent (RIPK4low) manner depending on cell origin (distant or lymph node metastasis) or phenotype (mesenchymal or epithelial).
Highlights
The receptor-interacting serine/threonine kinase protein 4 (RIPK4, known as DIK or PKK) is a highly conserved member of the RIP family of serine-threonine kinases containing an N-terminal RIP-like kinase domain and a C-terminal region characterized by 11 ankyrin repeats [1,2]
There is no evidence that receptor-interacting protein kinase 4 (RIPK4) plays any role in melanoma, we first investigated its level in established melanoma cell lines, patient-derived melanoma cell lines and clinical samples
Much higher mRNA and protein levels of RIPK4 were observed in the melanoma cells derived from lymph node metastasis (WM266.4) when compared to WM115 cells that were derived from primary melanoma of the same patient
Summary
The receptor-interacting serine/threonine kinase protein 4 (RIPK4, known as DIK or PKK) is a highly conserved member of the RIP family of serine-threonine kinases containing an N-terminal RIP-like kinase domain and a C-terminal region characterized by 11 ankyrin repeats [1,2]. Mutations in RIPK4, including loss-of-function mutation, have been detected in keratinocytes of patients with Bartsocas-Papas syndrome [4,5]. The observed deformations of RIPK4 KO mice are phenotypically similar to IKK (I kappa B kinase) KO mice, suggesting that RIPK4 is involved in NF-κB-dependent keratinocyte differentiation [6,7]. These findings are in contrast to conflicting data on the RIPK4 role in cancer [7]. Despite the role of RIPK4 in skin homeostasis [7], its function in melanoma progression has not yet been investigated
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