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Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
Published on: August 9, 2019
Heterogeneous nuclear ribonucleoprotein A2 is a SET-binding protein and a PP2A inhibitor
J Vera1, M Jaumot, J M Estanyol
1Department of Cell Biology and Pathology, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
Abstract:
The oncoprotein SET participates in a diversity of cellular functions including cell proliferation. Its role on cell cycle progression is likely mediated by inhibiting cyclin B-cdk1 and the protein phosphatase 2A (PP2A). On identifying new SET cellular partners, we found that SET interacts in vitro and in vivo with the heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2); a protein involved in various aspects of mRNA biogenesis. The SET-binding region of hnRNPA2 is the RNP1 sequence that belongs to the RNA-binding domain (RBD) of this protein. We also found that hnRNPA2 has much higher affinity for single-standed DNA than for SET. On analysing the effect of hnRNPA2 on PP2A inhibition by SET, we observed that hnRNPA2 cooperates with SET on PP2A inhibition. This is because we found that hnRNPA2 is also a PP2A inhibitor. HnRNPA2 interacts with PP2A by the RNP1 sequence; however, to inhibit PP2A activity, the complete RBD is needed. We also observed that overexpression of hnRNPA2 inhibits PP2A activity and stimulates cell proliferation. Interestingly, the overexpression of the complete RBD is sufficient to stimulate proliferation. As hnRNPA2 is overexpressed in a variety of human tumors, our results suggest that hnRNPA2 might participate in oncogenesis by stimulating cell proliferation.
Insights
The oncoprotein SET and hnRNPA2 protein cooperate to inhibit PP2A, stimulating cell proliferation. Overexpression of hnRNPA2 may drive oncogenesis by promoting cell growth.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The oncoprotein SET regulates cell proliferation, likely by inhibiting cyclin B-cdk1 and protein phosphatase 2A (PP2A).
- Heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) is involved in mRNA biogenesis.
Purpose of the Study:
- To investigate the interaction between SET and hnRNPA2.
- To elucidate the role of hnRNPA2 in PP2A inhibition and cell proliferation.
Main Methods:
- In vitro and in vivo interaction studies between SET and hnRNPA2.
- Analysis of hnRNPA2's effect on PP2A activity.
- Cell proliferation assays upon hnRNPA2 overexpression.
Main Results:
- SET interacts with hnRNPA2 via its RNP1 sequence within the RNA-binding domain (RBD).
- hnRNPA2 inhibits PP2A activity, cooperating with SET, and requires its complete RBD for inhibition.
- Overexpression of hnRNPA2, particularly its RBD, stimulates cell proliferation.
Conclusions:
- hnRNPA2 acts as a PP2A inhibitor and promotes cell proliferation.
- hnRNPA2's role in PP2A inhibition and cell proliferation suggests its potential involvement in oncogenesis, especially given its overexpression in tumors.
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