Regulation of the AKAP79-Protein Kinase C Interaction by Ca2+/Calmodulin

Faux, Maree C.; Scott, John D.

doi:10.1074/jbc.272.27.17038

Cited by 111 publications

(100 citation statements)

References 40 publications

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“…In the case of AKAP-79 it has been shown that depletion of calcium does not influence the binding of PKC and that the binding of Ca 2ϩ /calmodulin reciprocally affects PKC binding (33). This indicates that the calcium-dependence of the gravin/PKC␣ and the AKAP-79/PKC interaction are clearly different.…”

Section: Discussionmentioning

confidence: 77%

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Differential and Regulated Binding of cAMP-dependent Protein Kinase and Protein Kinase C Isoenzymes to Gravin in Human Model Neurons

Piontek

Brandt

2003

Journal of Biological Chemistry

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The membrane cortex has an important role in generating and maintaining spatially and functionally distinct domains in neurons. As a tool to functionally characterize molecules of the membrane cortex, we generated novel monoclonal antibodies against a fraction enriched for components of the neuronal membrane skeleton. We obtained two antibodies against the kinase-anchoring protein gravin. Gravin was strongly up-regulated during differentiation of human model neurons (NT2-N neurons) and was enriched at the inner peripheral cortex in close proximity to the plasma membrane where its localization primarily depended on association with membranes. In differentiated neurons, gravin colocalized in putative signaling complexes with protein kinase C (PKC␤II) and partially with PKC␣ and cAMP-dependent protein kinase (PKA). Colocalization with PKC⑀ was not observed. PKC␤II, PKC␣, and PKA but not PKC⑀ coprecipitated with gravin indicating physical interaction. Binding of gravin to PKC␣ required the presence of Ca 2؉ and was increased after inhibition of PKC. In contrast, binding of PKC␤II and PKA were independent of Ca 2؉ and PKC inhibition. Activation of PKC decreased binding of PKC␣ to gravin, decreased its association with the plasma membrane, and reduced the mean size of gravin particles. Taken together the data suggest that gravin provides a dynamic platform to localize kinases in an isoenzyme-specific and activation-dependent manner at specific sites in neurons.During development, many neurons establish a complex morphology that is characterized by the formation of multiple and in many cases highly branched neurites. Within the neurites, many organelles and proteins exhibit a nonuniform distribution that is thought to provide the basis for the formation of structurally and functionally distinct domains. For example, mitochondria are clustered at sites of high energy consumption, and several cytoskeleton-associated proteins are enriched at positions where active process outgrowth occurs. Some kinases and phosphatases also show a nonuniform distribution in neurons and are enriched at specific regions. In many cases this is achieved by locally anchoring them to cytosolic filament systems or to components of the cortical membrane skeleton.

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Section: Discussionmentioning

confidence: 77%

“…Because phosphatidylserine (PS) and Ca 2ϩ are cofactors for the activity of PKC, they may also be involved in the binding of PKC to anchoring proteins (11,33). However, addition of exogenous PS did not affect the amount of coprecipitated kinases (Fig.…”

Section: Pkc Differentially Binds To Gravin In An Isoenzyme- Ca 2ϩ -mentioning

confidence: 99%

Differential and Regulated Binding of cAMP-dependent Protein Kinase and Protein Kinase C Isoenzymes to Gravin in Human Model Neurons

Piontek

Brandt

2003

Journal of Biological Chemistry

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“…2b). Agonist-dependent rundown of GluR1 currents was sustained in cells expressing AKAP150ΔPKA (Δ675-697) and AKAP150ΔPKC (Δ31-51) deletion mutants that are unable to anchor PKA or PKC, respectively [14][15][16] (Fig. 2c, d).…”

Section: Functional Characterization Of Akap79-depleted Cellsmentioning

confidence: 99%

Distinct enzyme combinations in AKAP signalling complexes permit functional diversity

2005

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Specificity in cell signalling can be influenced by the targeting of different enzyme combinations to substrates. The A-kinase anchoring protein AKAP79/150 is a multivalent scaffolding protein that coordinates the subcellular localization of second-messenger-regulated enzymes, such as protein kinase A, protein kinase C and protein phosphatase 2B. We developed a new strategy that combines RNA interference of the endogenous protein with a protocol that selects cells that have been rescued with AKAP79/150 forms that are unable to anchor selected enzymes. Using this approach, we show that AKAP79/150 coordinates different enzyme combinations to modulate the activity of two distinct neuronal ion channels: AMPA-type glutamate receptors and M-type potassium channels. Utilization of distinct enzyme combinations in this manner provides a means to expand the repertoire of cellular events that the same AKAP modulates.Cellular regulation must be accomplished through the synchronized actions of a limited number of gene products, as the number of mammalian genes that are required to sustain life is significantly less than was originally anticipated 1,2 . Signal-transduction pathways are created when enzymes, often with broad substrate specificities, act sequentially to evoke cellular responses 3 . Restricting the subcellular localization of these enzymes with scaffolding proteins contributes to the fidelity of each response 4 . Prototypic examples of these are the A-kinase anchoring proteins (AKAPs) that target the cyclic-AMP-dependent protein kinase (protein kinase A, PKA) and other enzymes to defined subcellular locations 5 .AKAP signalling complexes often include signal-transduction and signal-termination enzymes to regulate the forward and backward steps of a given process. The notion of multivalent anchoring proteins was first proposed for the AKAP79 family, which consists of a group of three structurally similar orthologues: human AKAP79, murine AKAP150 and bovine AKAP75 (ref. 6). These AKAPs contain binding sites for PKA, the calcium/ phospholipid-dependent kinase (protein kinase C, PKC) and the calcium/calmodulindependent phosphatase (protein phosphatase 2B, PP2B) 7 . They are tethered to the inner face of the plasma membrane, where they can respond to the generation of second messengers, such as cAMP, calcium and phospholipid 7 . Functional studies have shown that this AKAP family controls the phosphorylation status and action of several ion channels, including AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors, L-type calcium channels, aquaporin water channel, and M-type potassium channels [8][9][10] . One theory that accounts for this diversity of action is that unique combinations of anchored enzymes are recruited to individual ion channels. We tested this hypothesis in cells in which the endogenous anchoring protein was silenced and replaced with AKAP forms that were unable to anchor selected binding partners. Results Functional characterization of AKAP79-depleted cellsPl...

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“…In AKAP79, the sequence K 31 ASMLC-FKRRKKAAKALKPKAG 52 (where the bold residues represent the dibasic residue motif) also has been implicated as a CaMbinding domain, as well as a weak PKCβII-binding site [37]. The first 150 residues of AKAP79 include several clusters of hydrophobic and basic charged residues proposed to function as a 'polybasic membrane-targeting domain' [7].…”

Section: Marcks Protein Membrane Effector-like Domainmentioning

confidence: 99%

“…For AKAP250, in vitro studies of the ability of various regions of this scaffold to bind purified PKCβII in a phospholipiddependent manner identified PKC-binding somewhere within residues 265-556 of AKAP250. The possibility that PKC, CaN [37] and, perhaps, CaM can compete for binding to a common region is extremely provocative. Detailed study of the interactions of AKAP79/250 with these potentially competing signalling molecules remains an important goal for the investigation of this tantalizing hypothesis.…”

Section: Multivalent Pkc/cam/can-binding Sitementioning

confidence: 99%

AKAPs (A-kinase anchoring proteins) and molecules that compose their G-protein-coupled receptor signalling complexes

Malbon

Tao

Wang

2004

Biochemical Journal

100

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Cell signalling mediated via GPCRs (G-protein-coupled receptors) is a major paradigm in biology, involving the assembly of receptors, G-proteins, effectors and downstream elements into complexes that approach in design 'solid-state' signalling devices. Scaffold molecules, such as the AKAPs (A-kinase anchoring proteins), were discovered more than a decade ago and represent dynamic platforms, enabling multivalent signalling. AKAP79 and AKAP250 were the first to be shown to bind to membrane-embedded GPCRs, orchestrating the interactions of various protein kinases (including tyrosine kinases), protein phosphatases (e.g. calcineurin) and cytoskeletal elements with at least one member of the superfamily of GPCRs, the prototypical β 2 -adrenergic receptor. In this review, the multivalent interactions of AKAP250 with the cell membrane, receptor, cytoskeleton and constituent components are detailed, providing a working model for AKAP-based GPCR signalling complexes. Dynamic regulation of the AKAP-receptor complex is mediated by ordered protein phosphorylation.

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Regulation of the AKAP79-Protein Kinase C Interaction by Ca2+/Calmodulin

Cited by 111 publications

References 40 publications

Differential and Regulated Binding of cAMP-dependent Protein Kinase and Protein Kinase C Isoenzymes to Gravin in Human Model Neurons

Differential and Regulated Binding of cAMP-dependent Protein Kinase and Protein Kinase C Isoenzymes to Gravin in Human Model Neurons

Distinct enzyme combinations in AKAP signalling complexes permit functional diversity

AKAPs (A-kinase anchoring proteins) and molecules that compose their G-protein-coupled receptor signalling complexes

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