Regulating the regulator: Insights into the cardiac protein phosphatase 1 interactome.
Reversible phosphorylation of proteins is a delicate yet dynamic balancing act between kinases and phosphatases, the disturbance of which underlies numerous disease processes. While our understanding of protein kinases has grown tremendously over the past decades, relatively little is known regarding protein phosphatases. This may be because protein kinases are great in number and relatively specific in function, and thereby amenable to be studied in isolation, whereas protein phosphatases are much less abundant and more nonspecific in their function. To achieve subcellular localization and substrate specificity, phosphatases depend on partnering with a large number of regulatory subunits, protein scaffolds and/or other interactors. This added layer of complexity presents a significant barrier to their study, but holds the key to unexplored opportunities for novel pharmacologic intervention. In this review we focus on serine/threonine protein phosphatase type-1 (PP1), which plays an important role in cardiac physiology and pathophysiology. Although much work has been done to investigate the role of PP1 in cardiac diseases including atrial fibrillation and heart failure, most of these studies were limited to examining and manipulating the catalytic subunit(s) of PP1 without adequately considering the PP1 interactors, which give specificity to PP1's functions. To complement these studies, three unbiased methods have been developed and applied to the mapping of the PP1 interactome: bioinformatics approaches, yeast two-hybrid screens, and affinity-purification mass spectrometry. The application of these complementary methods has the potential to generate a detailed cardiac PP1 interactome, which is an important step in identifying novel and targeted pharmacological interventions.
Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
David Y
DY
Chiang
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Albert J R
AJ
Heck
Institute of Pharmacology, University Duisburg/Essen, Essen, Germany.
Dobromir
D
Dobrev
Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA; Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, TX, USA. Electronic address: wehrens@bcm.edu.
Xander H T
XH
Wehrens
D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods; D054645:Protein Phosphatase 1 / Q000378:metabolism*
D002352:Carrier Proteins; D054645:Protein Phosphatase 1
Atrial fibrillation; Heart failure; Protein phosphatase; Proteomics; Regulatory subunit
Circ Res. 1999 Oct 29;85(9):848-55
10532953
Am J Physiol Heart Circ Physiol. 2002 Sep;283(3):H1092-8
12181139
FEBS J. 2013 Jan;280(2):584-95
22360570
J Cell Biol. 2006 Feb 27;172(5):679-92
16492807
Cardiovasc Res. 2008 Aug 1;79(3):464-71
18453636
Circulation. 2014 Jan 14;129(2):145-56
24249718
BMC Genomics. 2016 Mar 17;17 :246
26988354
Mol Cell Biol. 2002 Jun;22(12):4124-35
12024026
Biochem J. 2011 Apr 1;435(1):73-83
21222654
Biochem Biophys Res Commun. 2010 Jan 1;391(1):698-702
19945436
Science. 2011 Apr 1;332(6025):91-4
21385720
Naunyn Schmiedebergs Arch Pharmacol. 2007 Aug;375(6):383-92
17593353
Cardiovasc Res. 2005 Oct 1;68(1):98-108
15975567
J Mol Biol. 2006 Nov 24;364(2):196-212
17007873
J Biol Chem. 2003 May 23;278(21):18817-23
12657641
Biochem Biophys Res Commun. 2007 May 11;356(3):594-8
17374523
J Clin Invest. 2014 Nov;124(11):4759-72
25329692
J Mol Cell Cardiol. 2009 Mar;46(3):385-94
19100271
Cardiovasc Res. 2014 Jul 1;103(1):178-87
24812280
J Biol Chem. 2004 Aug 27;279(35):37079-86
15226296
Circ Arrhythm Electrophysiol. 2010 Oct;3(5):530-41
20660541
Circulation. 2006 Aug 15;114(7):670-80
16894034
Circ Arrhythm Electrophysiol. 2008 Jun 1;1(2):93-102
19808399
Chem Biol. 2009 Apr 24;16(4):365-71
19389623
Am J Physiol Heart Circ Physiol. 2003 Dec;285(6):H2373-81
14613911
Circulation. 2014 Mar 25;129(12):1276-85
24398018
J Mol Cell Cardiol. 2015 Oct;87:204-13
26334248
OMICS. 2012 Jan-Feb;16(1-2):3-17
22321011
Chem Biol. 2006 Jan;13(1):49-59
16426971
J Cell Biol. 2001 May 14;153(4):699-708
11352932
Biochem Pharmacol. 2011 Nov 15;82(10):1403-15
21382349
Physiol Rev. 2004 Jan;84(1):1-39
14715909
Cardiovasc Res. 2008 Dec 1;80(3):396-406
18689792
J Am Coll Cardiol. 2015 Jan 20;65(2):163-73
25593058
Circ Res. 2009 Apr 24;104(8):1012-20
19299645
J Mol Neurosci. 2013 May;50(1):179-97
23080069
J Mol Cell Cardiol. 1997 Jan;29(1):265-72
9040041
Circulation. 2004 Oct 26;110(17):2651-7
15492323
Biochemistry. 2012 Dec 4;51(48):9678-88
23140390
Biochemistry. 2002 Feb 19;41(7):2409-20
11841235
Cardiovasc Res. 2004 Jan 1;61(1):87-93
14732205
J Clin Invest. 2010 Feb;120(2):617-26
20071777
J Mol Cell Cardiol. 2008 Dec;45(6):846-52
18848565
Cardiovasc Res. 2011 Jan 1;89(1):79-88
20675715
Circ Res. 2012 May 25;110(11):1474-83
22511749
Biochemistry. 2007 Apr 17;46(15):4635-44
17381077
Chem Biol. 2006 Jan;13(1):6-8
16426965
Proteomics. 2007 Sep;7(17):3207-18
17683050
J Clin Invest. 2009 Jul;119(7):1940-51
19603549
Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1539-46
18689497
EMBO J. 1997 Apr 15;16(8):1876-87
9155014
Cell. 2009 Oct 30;139(3):468-84
19879837
J Mol Cell Cardiol. 2013 Nov;64:90-8
24051368
Expert Rev Proteomics. 2015 Apr;12(2):147-58
25795147
Circ Res. 2005 Apr 15;96(7):756-66
15746443
BMC Biochem. 2008 Nov 10;9:28
19000314