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Published on: March 8, 2022
Mechanisms underlying melanoma invasion as a consequence of MLK3 loss
Henriette U Balinda1, Alanna Sedgwick1, Crislyn D'Souza-Schorey1
1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, 46556-0369, USA.
Abstract:
Invasive melanoma is an aggressive form of skin cancer with high incidence of mortality. The process of tumor invasion is a crucial primary step in the metastatic cascade, yet the mechanisms involved are still under investigation. Here we document a critical role for MLK3 (MAP3K11) in the regulation of melanoma cell invasion. We report the unexpected finding that cellular loss of MLK3 in melanoma cells promotes cell invasion. Cellular depletion of MLK3 expression results in the hyperactivation of ERK, which is linked to the formation of a BRAF/Hsp90/Cdc37 protein complex. ERK hyperactivation leads to enhanced phosphorylation and inactivation of GSK3β and the stabilization of c-Jun and JNK activity. Blocking of ERK and JNK signaling as well as Hsp90 activity downstream of MLK3-silencing significantly reduces melanoma invasion. Furthermore, ERK activation in the aforementioned context is coupled to MT1-MMP transcription as well as the TOM1L1-dependent localization of the membrane protease to invadopodia at the invasive front. These studies provide critical insight into the mechanisms that couple MLK3 loss with BRAF hyperactivation and its consequence on melanoma invasion.
Insights
Loss of MLK3 (MAP3K11) surprisingly enhances melanoma cell invasion by activating ERK signaling. This pathway involves BRAF, Hsp90, and GSK3β, ultimately promoting tumor spread.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Melanoma invasion is a critical step in metastasis, yet its regulatory mechanisms remain incompletely understood.
- Mitogen-activated protein kinase kinase kinase 3 (MLK3) is implicated in cellular signaling pathways, but its specific role in melanoma invasion requires further elucidation.
Purpose of the Study:
- To investigate the role of MLK3 in regulating melanoma cell invasion.
- To elucidate the molecular mechanisms by which MLK3 influences melanoma cell motility and metastasis.
Main Methods:
- Utilized gene silencing techniques to deplete MLK3 expression in melanoma cells.
- Analyzed the activation status of key signaling proteins including ERK, JNK, and GSK3β.
- Investigated protein complex formation involving BRAF, Hsp90, and Cdc37.
- Assessed the transcriptional regulation of MT1-MMP and its localization to invadopodia.
Main Results:
- Unexpectedly, MLK3 depletion led to hyperactivation of ERK signaling in melanoma cells.
- ERK hyperactivation was associated with BRAF/Hsp90/Cdc37 complex formation, GSK3β inactivation, and c-Jun/JNK stabilization.
- Inhibition of ERK, JNK, and Hsp90 significantly reduced melanoma cell invasion.
- ERK activation correlated with increased MT1-MMP transcription and its localization to invadopodia.
Conclusions:
- MLK3 plays a critical regulatory role in controlling melanoma cell invasion.
- Loss of MLK3 promotes invasion through a pathway involving BRAF hyperactivation, ERK/JNK signaling, and MT1-MMP localization.
- These findings offer novel insights into melanoma metastasis mechanisms and potential therapeutic targets.
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