Multiple pathways control protein kinase C phosphorylation - PubMed (original) (raw)

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Multiple pathways control protein kinase C phosphorylation

D B Parekh et al. EMBO J. 2000.

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Fig. 1. The classical pathway of PKC activation. The scheme illustrates the production of the immediate precursor lipid PtdIns(4,5)P2 from its parent lipid PtdIns. Various agonists are linked to the phospholipases (PtdIns-PLC) that can cleave PtdIns(4,5)P2 to diacylglycerol (DAG) and the calcium mobilizer Ins(1,4,5)P3. Calcium can affect the cPKC class by promoting membrane recruitment, but the key allosteric activator at the membrane for both cPKC and nPKC isotypes is DAG.

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Fig. 2. Model for the phosphorylation of PKC. PKC is represented by a regulatory domain, comprising a C1 domain, C2 domain and pseudosubstrate site (black circle) and a catalytic domain (C3/4) with a C-terminal, V5, extension. The unphosphorylated primary translation product is predicted to have little or no activity. On ligand binding at the membrane, PKC becomes a substrate for kinases acting upon activation loop sites (for PKCα the T497 site) and hydrophobic C–terminal sites (for PKCα the S657 site). Following subsequent autophosphorylation (for PKCα the T638 site), the kinase domain is in a closed conformation that confers stability and phosphatase resistance. Ligand dissociation allows the kinase to diffuse away from the membrane but to remain in a phosphorylated state. The latent kinase can then be recruited back to the membrane and reactivated by DAG alone.

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Fig. 3. AGC kinase domain alignment. The kinase domains of PKCα/δ/ζ, the PKC-related kinase PRK1, PKBα and p70S6kinase α (p70α) are aligned from their first conserved kinase sub-domain (I) through sub-domain X, to the region covering the C-terminal extension. The kinase sub-domains are indicated by the shaded areas, with regions I–X displayed with an increasingly darker hue. The three phosphorylation sites (or acidic residues) discussed in the text are indicated by the red bars. The activation loop is indicated by the dark purple block, and the hydrophobic C-terminal phosphorylation site is also boxed in dark purple.

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Fig. 4. Rho-dependent PRK activation via PDK1. In the unliganded state, PRK is shown to be in an inactive conformation, with the pseudosubstrate site(s) in the HR1 domain interacting with the catalytic domain. On Rho binding to the HR1 motif in a membrane compartment, the kinase domain is released and can express catalytic activity, albeit at a low level. The exposed kinase domain can interact with PDK1 through its PIF motif (see text) and, on its association with PtdIns(3,4,5)P3, PDK1 will phosphorylate and activate PRK. The domains illustrated are summarized in the figure.

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Fig. 5. A general scheme of PKC controls. The figure illustrates the upstream inputs to membrane recruitment and phosphorylation of PKC that are required to generate the ‘mature’ phosphorylated form. For reasons of clarity, this is a simplified view of the process that excludes the action of PKC-interacting proteins that are likely to play roles in localization and membrane targeting. Some of the inhibitors that can block specific steps in the input pathways are included (in red), as well as the kinases and phosphatases (undefined) predicted to play key roles in effecting the modifications. External influences are known to control many of these steps, including activation of PtdIns-PLC, PtdIns 3-kinase and mTOR. Inputs to the aPKC complex (?) are as yet undefined.

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