The activities of PP1 (protein phosphatase 1), a principal cellular phosphatase that reverses serine/threonine protein phosphorylation, can be altered by inhibitors whose activities are themselves regulated by phosphorylation. We now describe a novel PKC (protein kinase C)-dependent PP1 inhibitor, namely GBPI (gut and brain phosphatase inhibitor). The shorter mRNA that encodes this protein, GBPI-1, is expressed in brain, stomach, small intestine, colon and kidney, whereas a longer GBPI-2 splice variant mRNA is found in testis. Human GBPI-1 mRNA encodes a 145-amino-acid, 16.5 kDa protein with pI 7.92. GBPI contains a consensus PP1-binding motif at residues 21–25 and consensus sites for phosphorylation by enzymes, including PKC, PKA (protein kinase A or cAMP-dependent protein kinase) and casein kinase II. Recombinant GBPI-1-fusion protein inhibits PP1 activity with IC50=3 nM after phosphorylation by PKC. Phospho-GBPI can even enhance PP2A activity by >50% at submicromolar concentrations. Non-phosphorylated GBPI-1 is inactive in both assays. Each of the mutations in amino acids located in potential PP1-binding sequences, K21E+K22E and W25A, decrease the ability of GBPI-1 to inhibit PP1. Mutations in the potential PKC phosphoacceptor site T58E also dramatically decrease the ability of GBPI-1 to inhibit PP1. Interestingly, when PKC-phosphorylated GBPI-1 is further phosphorylated by PKA, it no longer inhibits PP1. Thus, GBPI-1 is well positioned to integrate PKC and PKA modulation of PP1 to regulate differentially protein phosphorylation patterns in brain and gut. GBPI, its closest family member CPI (PKC-potentiated PP1 inhibitor) and two other family members, kinase-enhanced phosphatase inhibitor and phosphatase holoenzyme inhibitor, probably modulate integrated control of protein phosphorylation states in these and other tissues.
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January 2004
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Research Article|
January 01 2004
GBPI, a novel gastrointestinal- and brain-specific PP1-inhibitory protein, is activated by PKC and inactivated by PKA
Qing-Rong LIU;
Qing-Rong LIU
*Molecular Neurobiology Branch, National Institute on Drug Abuse–Intramural Research Program (NIDA–IRP), NIH, Department of Health and Human Services (DHSS), Box 5180, Baltimore, MD 21224, U.S.A.
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Ping-Wu ZHANG;
Ping-Wu ZHANG
*Molecular Neurobiology Branch, National Institute on Drug Abuse–Intramural Research Program (NIDA–IRP), NIH, Department of Health and Human Services (DHSS), Box 5180, Baltimore, MD 21224, U.S.A.
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Zhicheng LIN;
Zhicheng LIN
*Molecular Neurobiology Branch, National Institute on Drug Abuse–Intramural Research Program (NIDA–IRP), NIH, Department of Health and Human Services (DHSS), Box 5180, Baltimore, MD 21224, U.S.A.
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Qi-Fu LI;
Qi-Fu LI
†Laboratory for Cell Biology and Tumor Cell Engineering, Xiamen University, Xiamen, Fujian 361005, People's Republic of China
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Amina S. WOODS;
Amina S. WOODS
‡Chemistry and Drug Metabolism Section, National Institute on Drug Abuse–Intramural Research Program (NIDA–IRP), NIH, Department of Health and Human Services (DHSS), Box 5180, Baltimore, MD 21224, U.S.A.
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Juan TRONCOSO;
Juan TRONCOSO
§Department of Pathology (Neuropathology), Johns Hopkins School of Medicine, Baltimore, MD 21287, U.S.A.
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George R. UHL
George R. UHL
1
*Molecular Neurobiology Branch, National Institute on Drug Abuse–Intramural Research Program (NIDA–IRP), NIH, Department of Health and Human Services (DHSS), Box 5180, Baltimore, MD 21224, U.S.A.
1To whom correspondence should be addressed (e-mail guhl@intra.nida.nih.gov).
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Publisher: Portland Press Ltd
Received:
January 15 2003
Revision Received:
September 10 2003
Accepted:
September 16 2003
Accepted Manuscript online:
September 16 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2004
2004
Biochem J (2004) 377 (1): 171–181.
Article history
Received:
January 15 2003
Revision Received:
September 10 2003
Accepted:
September 16 2003
Accepted Manuscript online:
September 16 2003
Citation
Qing-Rong LIU, Ping-Wu ZHANG, Zhicheng LIN, Qi-Fu LI, Amina S. WOODS, Juan TRONCOSO, George R. UHL; GBPI, a novel gastrointestinal- and brain-specific PP1-inhibitory protein, is activated by PKC and inactivated by PKA. Biochem J 1 January 2004; 377 (1): 171–181. doi: https://doi.org/10.1042/bj20030128
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