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Protein phosphatase 4--from obscurity to vital functions
Patricia T W Cohen1, Amanda Philp, Cristina Vázquez-Martin
1Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, UK. p.t.w.cohen@dundee.ac.uk
FEBS Letters
|May 26, 2005
Summary
Protein phosphatase 4 (Ppp4) regulates diverse cellular functions, including organelle and spliceosome assembly. This phosphatase also impacts DNA damage response and chromatin activity, and its inhibition by anticancer drugs suggests therapeutic potential.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Protein phosphatase 4 (Ppp4) is a serine/threonine phosphatase in the PPP family.
- It regulates cellular functions independently of protein phosphatase 2A (PP2A).
- Mammalian Ppp4 has regulatory subunits (R1 and R2) that interact with the catalytic subunit (Ppp4c) to control activity.
Purpose of the Study:
- To elucidate the diverse cellular roles of Ppp4.
- To investigate Ppp4's involvement in organelle and spliceosomal assembly.
- To explore Ppp4's function in DNA damage response, chromatin regulation, and its interaction with anticancer agents.
Main Methods:
- Investigated Ppp4 function through its interactions with regulatory subunits (R1, R2) and the catalytic subunit (Ppp4c).
- Examined Ppp4's role in centrosome and spliceosome assembly, including interactions with the SMN complex.
- Studied Ppp4's involvement in signaling pathways (NF-kappaB, TOR) and DNA damage response.
- Assessed Ppp4's impact on histone deacetylase activity and chromatin regulation.
- Analyzed the inhibitory effects of anticancer agents (cantharidin, fostriecin) on Ppp4 activity.
- Evaluated the role of Ppp4 orthologues in yeast resistance to DNA-binding anticancer drugs (cisplatin, oxaliplatin).
Main Results:
- Ppp4c-R2 complexes are crucial for centrosome maturation and spliceosomal assembly via the SMN complex.
- Ppp4 regulates NF-kappaB and TOR signaling pathways.
- Ppp4 is implicated in DNA damage response and chromatin regulation through histone deacetylase inhibition by Ppp4c-R1 complexes.
- Anticancer agents cantharidin and fostriecin inhibit Ppp4 activity.
- Yeast Ppp4 orthologues confer resistance to cisplatin and oxaliplatin.
Conclusions:
- Ppp4 is a multifunctional phosphatase involved in fundamental cellular processes.
- Its roles in organelle assembly, DNA damage response, and chromatin regulation highlight its significance.
- Ppp4's inhibition by anticancer drugs and its role in drug resistance suggest potential therapeutic applications.