Extracellular signal-regulated kinases associate with and phosphorylate DHPS to promote cell proliferation
Chao Wang1, Zhen Chen1, Litong Nie1
1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Abstract:
The ERK1/2 pathway is one of the most commonly dysregulated pathways in human cancers and controls many vital cellular processes. Although many ERK1/2 kinase substrates have been identified, the diversity of ERK1/2 mediated processes suggests the existence of additional targets. Here, we identified Deoxyhypusine synthase (DHPS), an essential hypusination enzyme regulating protein translation, as a major and direct-binding protein of ERK1/2. Further experiments showed that ERK1/2 phosphorylate DHPS at Ser-233 site. The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. Moreover, we found that higher DHPS expression correlated with poor prognosis in lung adenocarcinoma and increased resistance to inhibitors of the ERK1/2 pathway. In summary, our results suggest that ERK1/2-mediated DHPS phosphorylation is an important mechanism that underlies protein translation and that DHPS expression is a potent biomarker of response to therapies targeting ERK1/2-pathway.
Insights
The ERK1/2 pathway directly phosphorylates Deoxyhypusine synthase (DHPS), impacting cell proliferation. Increased DHPS expression indicates poor prognosis and resistance to ERK1/2 therapies in lung cancer.
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- The Extracellular signal-Regulated Kinase (ERK1/2) pathway is frequently altered in human cancers.
- While many ERK1/2 substrates are known, additional targets are suspected due to the pathway's diverse roles.
Purpose of the Study:
- To identify novel direct binding partners and substrates of ERK1/2.
- To investigate the functional significance of ERK1/2-mediated phosphorylation of Deoxyhypusine synthase (DHPS).
- To evaluate DHPS as a potential biomarker for cancer prognosis and therapeutic response.
Main Methods:
- Co-immunoprecipitation assays to identify ERK1/2 binding partners.
- In vitro kinase assays and site-directed mutagenesis to confirm phosphorylation site.
- Analysis of DHPS expression in lung adenocarcinoma patient cohorts.
- Correlation of DHPS expression with clinical outcomes and treatment response.
Main Results:
- Deoxyhypusine synthase (DHPS) was identified as a direct binding protein of ERK1/2.
- ERK1/2 phosphorylates DHPS at the Ser-233 residue, which is crucial for its function in cell proliferation.
- Elevated DHPS expression in lung adenocarcinoma correlates with poorer patient prognosis.
- Higher DHPS levels are associated with increased resistance to therapies targeting the ERK1/2 pathway.
Conclusions:
- ERK1/2-mediated phosphorylation of DHPS is a significant mechanism regulating protein translation and cell proliferation.
- DHPS serves as a potential predictive biomarker for patient response to ERK1/2 pathway-targeted therapies in lung cancer.
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