Protein serine/threonine phosphatases: life, death, and sleeping
Section snippets
Introduction: the importance of phosphatases
Reversible post-translation protein serine/threonine phosphorylation regulates virtually every signaling pathway in the eukaryotic cell. The net phosphorylation state and, potentially, the activity of every phosphoprotein are controlled by a balance between kinases and phosphatases. In the past two years, there have been notable steps forward in our understanding of the role of protein serine/threonine phosphatases (PSTPs) in processes ranging from circadian rhythms to DNA damage and apoptosis.
Protein phosphatase 1: regulatory subunits limit the options
The targeting subunits of the phosphoprotein phosphatase (PPP) family confer both substrate specificity and intracellular localization to the catalytic subunits. Several recent findings serve to highlight the critical biological functions of these targeting subunits.
The free catalytic subunits of the abundant protein phosphatases PP1 and PP2A have been referred to as promiscuous because of their high activity and low specificity. The phospho-monoester bond is incredibly stable at neutral pH,
Protein phosphatase 2A: life and death
Recent studies indicate that distinct forms of PP2A regulate development, cancer, apoptosis and circadian rhythm, to name just a few of the most prominent examples. PP2A makes up 0.1% of cellular protein, yet the catalytic subunit is encoded by only two highly conserved genes. Like PP1, the isolated PP2A catalytic subunit is highly active in vitro, and in vivo is regulated by formation of hetero-oligomers. By far the most abundant form is a heterotrimer containing a conserved A subunit and one
Protein phosphatase 5 and the response to stress
In humans, protein phosphatase 5 (PP5) is encoded by a single gene and its expression is ubiquitous. Unlike PP1 and PP2A, PP5 contains both regulatory and subcellular targeting functions within a single polypeptide chain. The catalytic domain of PP5 shares 35–45% sequence identity with the catalytic domains of other PPP phosphatases, and PP5 shares a common catalytic mechanism with PP1 and PP2B [26]. However, PP5 contains an extended N-terminal domain with three tetratricopeptide repeat motifs
Phosphatases in circadian rhythm
Circadian rhythm is an intrinsic ∼24 h oscillation of cellular and organismal function that proceeds in the absence of external stimuli. The molecular clock is run by a transcription–translation negative-feedback loop that requires periodic nuclear accumulation of transcriptional repressors. A role for serine/threonine phosphatases in the regulation of circadian rhythm was first proposed when Hastings and coworkers demonstrated that PP1 and PP2A inhibitors alter the circadian rhythm in the
Conclusions
Phosphatase regulatory subunits are the key control element in protein dephosphorylation. These regulatory subunits determine the exquisite substrate specificity of the phosphatase holoenzymes, the functional unit of PSTPs. To understand how phosphatases work, it will be critical to study specific phosphatase holoenzymes rather than considering catalytic subunits in isolation.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (43)
- et al.
Signaling by protein phosphatases in the nucleus
Trends Cell Biol
(2002) - et al.
Protein tyrosine phosphatases in the human genome
Cell
(2004) Combinatorial control of protein phosphatase-1
Trends Biochem Sci
(2001)- et al.
Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits
Proc Natl Acad Sci USA
(2002) - et al.
Identification of specific PP2A complexes involved in human cell transformation
Cancer Cell
(2004) - et al.
PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation
Mol Cell
(2003) - et al.
Identification of amino acids in the tetratricopeptide repeat and C-terminal domains of protein phosphatase 5 involved in autoinhibition and lipid activation
Biochemistry
(2001) - et al.
The tetratricopeptide repeat domain and a C-terminal region control the activity of Ser/Thr protein phosphatase 5
J Biol Chem
(1999) - et al.
Nuclear localization of protein phosphatase 5 is dependent on the carboxy-terminal region
FEBS Lett
(2001) - et al.
Requirement of protein phosphatase 5 in DNA-damage-induced ATM activation
Genes Dev
(2004)
Phosphatases join kinases in DNA-damage response pathways
Trends Cell Biol
Inhibition of mammalian target of rapamycin activates apoptosis signal-regulating kinase 1 signaling by suppressing protein phosphatase 5 activity
J Biol Chem
Ser/thr protein phosphatase 5 (PP5) inactivates hypoxia-induced activation of an ASK-1/MKK-4/JNK-signaling cascade
J Biol Chem
Inhibitors of serine/threonine phosphoprotein phosphatases alter circadian properties in Gonyaulax polyedra
Plant Physiol
Post-translational regulation of Drosophila PERIOD protein by protein phosphatase 2A
Cell
Calcium–calcineurin signaling in the regulation of cardiac hypertrophy
Biochem Biophys Res Commun
A novel RNA polymerase II C-terminal domain phosphatase that preferentially dephosphorylates serine 5
J Biol Chem
Protein phosphatase 1 — targeted in many directions
J Cell Sci
Regulators of serine/threonine protein phosphatases at the dawn of a clinical era?
Curr Med Chem
The protein kinase complement of the human genome
Science
The rate of hydrolysis of phosphomonoester dianions and the exceptional catalytic proficiencies of protein and inositol phosphatases
Proc Natl Acad Sci USA
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