Kinome profiling identifies MARK3 and STK10 as potential therapeutic targets in uveal melanoma
Usman Baqai1, Alison M Kurimchak2, Isabella V Trachtenberg1
1Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Abstract:
Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. A custom siRNA screen targeting these kinases demonstrated that knockdown of microtubule affinity regulating kinase 3 (MARK3) and serine/threonine kinase 10 (STK10) significantly reduced uveal melanoma cell growth and decreased expression of cell cycle proteins. Additionally, knockdown of MARK3 but not STK10 decreased ERK1/2 phosphorylation. Analysis of RNA-sequencing and proteomic data showed that Gαq signaling regulates STK10 expression and MARK3 activity. Our findings suggest an involvement of STK10 and MARK3 in the Gαq/11 oncogenic pathway and prompt further investigation into the specific roles and targeting potential of these kinases in uveal melanoma.
Insights
Researchers identified novel kinases, MARK3 and STK10, regulated by Gαq/11 signaling. Targeting these kinases may offer new therapeutic strategies for metastatic uveal melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- Uveal melanoma frequently harbors GNAQ/GNA11 mutations, activating MAPK signaling.
- Current targeted therapies for metastatic uveal melanoma are limited.
- The "dark kinome" represents a largely unexplored source of potential therapeutic targets.
Purpose of the Study:
- To identify novel kinases regulated by Gαq/11 signaling in uveal melanoma.
- To explore the therapeutic potential of targeting these newly identified kinases.
Main Methods:
- GNAQ-mutant uveal melanoma cell lines were treated with a Gαq/11 inhibitor (YM-254890).
- Kinase signaling proteomic screening was performed using multiplexed-kinase inhibitors and mass spectrometry.
- siRNA screens were used to assess the impact of kinase knockdown on cell growth and protein expression.
- RNA-sequencing and proteomic data were analyzed to understand Gαq signaling regulation of identified kinases.
Main Results:
- Downregulation of 22 kinases was observed upon Gαq/11 inhibition.
- Knockdown of MARK3 (microtubule affinity regulating kinase 3) and STK10 (serine/threonine kinase 10) significantly reduced uveal melanoma cell growth.
- MARK3 knockdown, but not STK10, decreased ERK1/2 phosphorylation.
- Gαq signaling was found to regulate STK10 expression and MARK3 activity.
Conclusions:
- STK10 and MARK3 are implicated in the Gαq/11 oncogenic pathway in uveal melanoma.
- These kinases represent potential novel therapeutic targets for metastatic uveal melanoma.
- Further investigation into MARK3 and STK10 is warranted for therapeutic development.
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