In a landmark study published in the “Molecular and Cellular Biology” journal, researchers have unveiled a novel signaling pathway implicating the critical role of GP78, an autocrine motility factor (AMF) receptor with ubiquitin ligase activity, in cancer cell proliferation and invasion. The study, titled “GP78 Cooperates with Dual-Specificity Phosphatase 1 to Stimulate Epidermal Growth Factor Receptor-Mediated Extracellular Signal-Regulated Kinase Signaling,” sheds new light on the molecular mechanics of tumor proliferation driven by aberrant activation of the extracellular signal-regulated kinase (ERK) via receptor tyrosine kinases.
DOI: 10.1128/MCB.00485-18
The research, conducted by a team from the Karmanos Cancer Institute, Wayne State University School of Medicine, and the Drug Discovery Institute, University of Pittsburgh, revealed GP78’s significance in epidermal growth factor receptor (EGFR)-mediated ERK activation—both paramount factors in tumor cell proliferation.
The Discovery
The activation of EGFR is a common event in the progression of various cancers. Upon stimulation by the epidermal growth factor (EGF), it sets off a cascade that leads to the activation of ERK, a protein that, when aberrantly activated, encourages tumor proliferation and invasion. The exact mechanisms governing this response have, until now, been incompletely understood.
This pivotal research delineates the role of GP78 in the activation of ERK. GP78, identified as an E3 ubiquitin ligase – a type of enzyme that attaches ubiquitin onto substrates leading to their degradation – has now been shown to interact with and promote the ubiquitination and subsequent degradation of dual-specificity phosphatase 1 (DUSP1), an enzyme known for its inhibitory effect on mitogen-activated protein kinases (MAPKs) like ERK. Subsequently, the degradation of DUSP1 results in the sustained activation of ERK and, thus, promotes cell proliferation, motility, and invasion.
Moreover, GP78 plays a dual role. Beyond its influence on DUSP1, GP78 preserves the activation status of EGFR. In GP78-deficient cells, EGF was unable to incite EGFR phosphorylation—a step that is key for its activation. By managing both EGFR and ERK activation, GP78 emerges as a molecular bridge fostering cancer cell proliferation and motility.
Implications for Cancer Therapy
This discovery emphasizes the multifaceted nature of cancer cell biology, detailing new pathways that can be targeted for therapeutic intervention. It leads to the intriguing possibility of developing new cancer treatments aimed at inhibiting GP78, thereby reducing ERK activation and impeding cancer cell proliferation and invasiveness.
References
1. Kho, D. H., Uddin, M. H., Chatterjee, M., Vogt, A., Raz, A., & Wu, G. S. (2019). GP78 Cooperates with Dual-Specificity Phosphatase 1 To Stimulate Epidermal Growth Factor Receptor-Mediated Extracellular Signal-Regulated Kinase Signaling. Molecular and Cellular Biology, 39(11), e00485-18. https://doi.org/10.1128/MCB.00485-18
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3. Franklin, C. C., & Kraft, A. S. (1997). Conditional expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1 preferentially inhibits p38 MAPK and stress-activated protein kinase in U937 cells. Journal of Biological Chemistry, 272, 16917–16923. https://doi.org/10.1074/jbc.272.27.16917
4. Shapiro, P. S., & Ahn, N. G. (1998). Feedback regulation of Raf-1 and mitogen-activated protein kinase kinases 1 and 2 by MAP kinase phosphatase-1 (MKP-1). Journal of Biological Chemistry, 273, 1788–1793. https://doi.org/10.1074/jbc.273.3.1788
5. Kidger, A. M., Rushworth, L. K., Stellzig, J., et al. (2017). Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling. Proceedings of the National Academy of Sciences, 114, E317–E326. https://doi.org/10.1073/pnas.1614684114
Keywords
1. GP78 cancer signaling
2. ERK activation mechanism
3. EGFR-mediated signaling
4. Dual-specificity phosphatase 1
5. Cancer cell proliferation pathway