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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Sajan, Mini P. Farese, Robert V. Ivey, Robert A. |
| Description | Author Affiliation: Ivey RA ( From the Medical and Research Services, James A. Haley Veterans Medical Center, Tampa, Florida 33612 and.); Sajan MP ( From the Medical and Research Services, James A. Haley Veterans Medical Center, Tampa, Florida 33612 and the Division of Endocrinology and Metabolism, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612.); Farese RV ( From the Medical and Research Services, James A. Haley Veterans Medical Center, Tampa, Florida 33612 and the Division of Endocrinology and Metabolism, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612 rfarese@health.usf.edu.) |
| Abstract | Atypical PKC (aPKC) isoforms are activated by the phosphatidylinositol 3-kinase product phosphatidylinositol 3,4,5-(PO4)3 (PIP3). How PIP3 activates aPKC is unknown. Although Akt activation involves PIP3 binding to basic residues in the Akt pleckstrin homology domain, aPKCs lack this domain. Here we examined the role of basic arginine residues common to aPKC pseudosubstrate sequences. Replacement of all five (or certain) arginine residues in the pseudosubstrate sequence of PKC-ι by site-directed mutagenesis led to constitutive activation and unresponsiveness to PIP3 in vitro or insulin in vivo. However, with the addition of the exogenous arginine-containing pseudosubstrate tridecapeptide to inhibit this constitutively active PKC-ι, PIP3-activating effects were restored. A similar restoration of responsiveness to PIP3 was seen when exogenous pseudosubstrate was used to inhibit mouse liver PKC-λ/ζ maximally activated by insulin or ceramide and a truncated, constitutively active PKC-ζ mutant lacking all regulatory domain elements and containing 'activating' glutamate residues at loop and autophosphorylation sites (Δ1-247/T410E/T560E-PKC-ζ). NMR studies suggest that PIP3 binds directly to the pseudosubstrate. The ability of PIP3 to counteract the inhibitory effects of the exogenous pseudosubstrate suggests that basic residues in the pseudosubstrate sequence are required for maintaining aPKCs in an inactive state and are targeted by PIP3 for displacement from the substrate-binding site during kinase activation. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 36 |
| Volume Number | 289 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2014-09-05 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Arginine Metabolism Isoenzymes Phosphatidylinositol Phosphates Protein Kinase C 3T3-L1 Cells Amino Acid Sequence Animals Genetics Blotting, Western Dose-Response Relationship, Drug Enzyme Activation Drug Effects Magnetic Resonance Spectroscopy Mice Mice, 129 Strain Mice, Inbred C57BL Molecular Sequence Data Mutagenesis, Site-Directed Peptides Phosphatidylinositol 4,5-Diphosphate Pharmacology Phosphatidylserines Phosphorylation Substrate Specificity Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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