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Commentary |
Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD15EH, Scotland, UK
Address for correspondence (e-mail: p.t.w.cohen{at}dundee.ac.uk)
Protein phosphatase 1 (PP1) is a major eukaryotic protein serine/threonine phosphatase that regulates an enormous variety of cellular functions through the interaction of its catalytic subunit (PP1c) with over fifty different established or putative regulatory subunits. Most of these target PP1c to specific subcellular locations and interact with a small hydrophobic groove on the surface of PP1c through a short conserved binding motif – the RVxF motif – which is often preceded by further basic residues. Weaker interactions may subsequently enhance binding and modulate PP1 activity/specificity in a variety of ways. Several putative targeting subunits do not possess an RVxF motif but nevertheless interact with the same region of PP1c. In addition, several ‘modulator’ proteins bind to PP1c but do not possess a domain targeting them to a specific location. Most are potent inhibitors of PP1c and possess at least two sites for interaction with PP1c, one of which is identical or similar to the RVxF motif.Regulation of PP1c in response to extracellular and intracellular signals occurs mostly through changes in the levels, conformation or phosphorylation status of targeting subunits. Understanding of the mode of action of PP1c complexes may facilitate development of drugs that target particular PP1c complexes and thereby modulate the phosphorylation state of a very limited subset of proteins.
Key words: PP1, Protein targeting, Insulin action, Smooth muscle contraction, Pre-mRNA splicing, AKAP, Neurabin, 53BP2
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R. Sacchetto, E. Bovo, A. Donella-Deana, and E. Damiani Glycogen- and PP1c-targeting Subunit GM Is Phosphorylated at Ser48 by Sarcoplasmic Reticulum-bound Ca2+-Calmodulin Protein Kinase in Rabbit Fast Twitch Skeletal Muscle J. Biol. Chem., February 25, 2005; 280(8): 7147 - 7155. [Abstract] [Full Text] [PDF]
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B. Lesage, M. Beullens, M. Nuytten, A. Van Eynde, S. Keppens, B. Himpens, and M. Bollen Interactor-mediated Nuclear Translocation and Retention of Protein Phosphatase-1 J. Biol. Chem., December 31, 2004; 279(53): 55978 - 55984. [Abstract] [Full Text] [PDF]
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E. C. Muly, P. Allen, M. Mazloom, Z. Aranbayeva, A. T. Greenfield, and P. Greengard Subcellular Distribution of Neurabin Immunolabeling in Primate Prefrontal Cortex: Comparison with Spinophilin Cereb Cortex, December 1, 2004; 14(12): 1398 - 1407. [Abstract] [Full Text] [PDF]
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D. C. Weiser, S. Sikes, S. Li, and S. Shenolikar The Inhibitor-1 C Terminus Facilitates Hormonal Regulation of Cellular Protein Phosphatase-1: FUNCTIONAL IMPLICATIONS FOR INHIBITOR-1 ISOFORMS J. Biol. Chem., November 19, 2004; 279(47): 48904 - 48914. [Abstract] [Full Text] [PDF]
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N. A. Tountas and D. L. Brautigan Migration and retraction of endothelial and epithelial cells require PHI-1, a specific protein-phosphatase-1 inhibitor protein J. Cell Sci., November 15, 2004; 117(24): 5905 - 5912. [Abstract] [Full Text] [PDF]
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I. Munoz, A. Ruiz, M. Marquina, A. Barcelo, A. Albert, and J. Arino Functional Characterization of the Yeast Ppz1 Phosphatase Inhibitory Subunit Hal3: A MUTAGENESIS STUDY J. Biol. Chem., October 8, 2004; 279(41): 42619 - 42627. [Abstract] [Full Text] [PDF]
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 C. Bouche, S. Serdy, C. R. Kahn, and A. B. Goldfine The Cellular Fate of Glucose and Its Relevance in Type 2 Diabetes Endocr. Rev., October 1, 2004; 25(5): 807 - 830. [Abstract] [Full Text] [PDF]
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N. Vereshchagina, D. Bennett, B. Szoor, J. Kirchner, S. Gross, E. Vissi, H. White-Cooper, and L. Alphey The Essential Role of PP1{beta} in Drosophila Is to Regulate Nonmuscle Myosin Mol. Biol. Cell, October 1, 2004; 15(10): 4395 - 4405. [Abstract] [Full Text] [PDF]
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R. J. Colbran Protein Phosphatases and Calcium/Calmodulin-Dependent Protein Kinase II-Dependent Synaptic Plasticity J. Neurosci., September 29, 2004; 24(39): 8404 - 8409. [Full Text] [PDF]
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L. Wells, L. K. Kreppel, F. I. Comer, B. E. Wadzinski, and G. W. Hart O-GlcNAc Transferase Is in a Functional Complex with Protein Phosphatase 1 Catalytic Subunits J. Biol. Chem., September 10, 2004; 279(37): 38466 - 38470. [Abstract] [Full Text] [PDF]
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D. J. Hartshorne, M. Ito, and F. Erdodi Role of Protein Phosphatase Type 1 in Contractile Functions: Myosin Phosphatase J. Biol. Chem., September 3, 2004; 279(36): 37211 - 37214. [Full Text] [PDF]
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C. Hrabchak and S. Varmuza Identification of the Spermatogenic Zip Protein Spz1 as a Putative Protein Phosphatase-1 (PP1) Regulatory Protein That Specifically Binds the PP1c{gamma}2 Splice Variant in Mouse Testis J. Biol. Chem., August 27, 2004; 279(35): 37079 - 37086. [Abstract] [Full Text] [PDF]
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K. V. Vijayan, Y. Liu, T.-T. Li, and P. F. Bray Protein Phosphatase 1 Associates with the Integrin {alpha}IIb Subunit and Regulates Signaling J. Biol. Chem., August 6, 2004; 279(32): 33039 - 33042. [Abstract] [Full Text] [PDF]
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M. Eto, T. Kitazawa, and D. L. Brautigan Phosphoprotein inhibitor CPI-17 specificity depends on allosteric regulation of protein phosphatase-1 by regulatory subunits PNAS, June 15, 2004; 101(24): 8888 - 8893. [Abstract] [Full Text] [PDF]
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L. C. Carmody, P. A. Bauman, M. A. Bass, N. Mavila, A. A. DePaoli-Roach, and R. J. Colbran A Protein Phosphatase-1{gamma}1 Isoform Selectivity Determinant in Dendritic Spine-associated Neurabin J. Biol. Chem., May 21, 2004; 279(21): 21714 - 21723. [Abstract] [Full Text] [PDF]
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P. B. Allen, A. T. Greenfield, P. Svenningsson, D. C. Haspeslagh, and P. Greengard Phactrs 1-4: A family of protein phosphatase 1 and actin regulatory proteins PNAS, May 4, 2004; 101(18): 7187 - 7192. [Abstract] [Full Text] [PDF]
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M. K. Dougherty and D. K. Morrison Unlocking the code of 14-3-3 J. Cell Sci., April 15, 2004; 117(10): 1875 - 1884. [Abstract] [Full Text] [PDF]
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G. A. Rameau, L.-Y. Chiu, and E. B. Ziff Bidirectional Regulation of Neuronal Nitric-oxide Synthase Phosphorylation at Serine 847 by the N-Methyl-D-aspartate Receptor J. Biol. Chem., April 2, 2004; 279(14): 14307 - 14314. [Abstract] [Full Text] [PDF]
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 H. T. Tran, A. Ulke, N. Morrice, C. J. Johannes, and G. B. G. Moorhead Proteomic Characterization of Protein Phosphatase Complexes of the Mammalian Nucleus Mol. Cell. Proteomics, March 1, 2004; 3(3): 257 - 265. [Abstract] [Full Text] [PDF]
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 K. Hirano, D. N. Derkach, M. Hirano, J. Nishimura, S. Takahashi, and H. Kanaide Transduction of the N-Terminal Fragments of MYPT1 Enhances Myofilament Ca2+ Sensitivity in an Intact Coronary Artery Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 464 - 469. [Abstract] [Full Text]
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Y. Yang, Q. He, P. Cheng, P. Wrage, O. Yarden, and Y. Liu Distinct roles for PP1 and PP2A in the Neurospora circadian clock Genes & Dev., February 1, 2004; 18(3): 255 - 260. [Abstract] [Full Text] [PDF]
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Z. Huang and S. Vijayaraghavan Increased Phosphorylation of a Distinct Subcellular Pool of Protein Phosphatase, PP1{gamma}2, During Epididymal Sperm Maturation Biol Reprod, February 1, 2004; 70(2): 439 - 447. [Abstract] [Full Text] [PDF]
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W. Shi, C. Sun, B. He, W. Xiong, X. Shi, D. Yao, and X. Cao GADD34-PP1c recruited by Smad7 dephosphorylates TGF{beta} type I receptor J. Cell Biol., January 19, 2004; 164(2): 291 - 300. [Abstract] [Full Text] [PDF]
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H. CEULEMANS and M. BOLLEN Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button Physiol Rev, January 1, 2004; 84(1): 1 - 39. [Abstract] [Full Text] [PDF]
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Z. Hilioti, D. A. Gallagher, S. T. Low-Nam, P. Ramaswamy, P. Gajer, T. J. Kingsbury, C. J. Birchwood, A. Levchenko, and K. W. Cunningham GSK-3 kinases enhance calcineurin signaling by phosphorylation of RCNs Genes & Dev., January 1, 2004; 18(1): 35 - 47. [Abstract] [Full Text] [PDF]
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