Mitochondria: A kinase anchoring protein 1, a signaling platform for mitochondrial form and function

Merrill, Ronald A.; Strack, Stefan

doi:10.1016/j.biocel.2013.12.012

Cited by 91 publications

(90 citation statements)

References 48 publications

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“…It is worth noting that recent studies have shown that the PKA/AKAP1/Drp1 complex also plays a role in mitochondrial function [17,28]. Further studies should be conducted to determine whether these two AKAPs, GSKIP and AKAP1, have competitive, cooperative or distinctive functions and to determine their corresponding locations in Drp1-dependent mitochondrial fission.…”

Section: A Model Of Gskip Gsk3β Pka Rii and Drp1 Interactionmentioning

confidence: 96%

GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis signaling in the regulation of mitochondrial elongation

Loh

Lin

Yang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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GSK3β binding of GSKIP affects neurite outgrowth, but the physiological significance of PKA binding to GSKIP remains to be determined. We hypothesized that GSKIP and GSK3β mediate cAMP/PKA/Drp1 axis signaling and modulate mitochondrial morphology by forming a working complex comprising PKA/GSKIP/GSK3β/Drp1. We demonstrated that GSKIP wild-type overexpression increased phosphorylation of Drp1 S637 by 7-8-fold compared to PKA kinase-inactive mutants (V41/L45) and a GSK3β binding-defective mutant (L130) under H2O2 and forskolin challenge in HEK293 cells, indicating that not only V41/L45, but also L130 may be involved in Drp1-associated protection of GSKIP. Interestingly, silencing either GSKIP or GSK3β but not GSK3α resulted in a dramatic decrease in Drp1 S637 phosphorylation, revealing that both GSKIP and GSK3β are required in this novel PKA/GSKIP/GSK3β/Drp1 complex. Moreover, overexpressed kinase-dead GSK3β-K85R, which retains the capacity to bind GSKIP, but not K85M which shows total loss of GSKIP-binding, has a higher Drp1 S637 phosphorylation similar to the GSKIP wt overexpression group, indicating that GSK3β recruits Drp1 by anchoring rather than in a kinase role. With further overexpression of either V41/L45P or the L130P GSKIP mutant, the elongated mitochondrial phenotype was lost; however, ectopically expressed Drp1 S637D, a phosphomimetic mutant, but not S637A, a non-phosphorylated mutant, restored the elongated mitochondrial morphology, indicating that Drp1 is a downstream effector of direct PKA signaling and possibly has an indirect GSKIP function involved in the cAMP/PKA/Drp1 signaling axis. Collectively, our data revealed that both GSKIP and GSK3β function as anchoring proteins in the cAMP/PKA/Drp1 signaling axis modulating Drp1 phosphorylation.

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Section: A Model Of Gskip Gsk3β Pka Rii and Drp1 Interactionmentioning

confidence: 96%

GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis signaling in the regulation of mitochondrial elongation

Loh

Lin

Yang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Several alternative splice forms of AKAPs exist in tissues of the heart, liver, kidney, brain, and skeletal muscle (11). Dependent on the specific N-terminal amino acids present in the spliced variants of AKAPs, these proteins cannot only scaffold different macromolecules, but also attain the ability to transfer these macromolecules to various subcellular compartments including the nucleus, plasma membrane, golgi apparatus, and endoplasmic reticulum (ER) (7,10).…”

Section: Localization Of Akap121 Isoforms and Their Functionsmentioning

confidence: 99%

Pivotal role of AKAP121 in mitochondrial physiology

Czachor

Failla

Lockey

et al. 2016

American Journal of Physiology-Cell Physiology

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In this Perspective, we discuss some recent developments in the study of the mitochondrial scaffolding protein AKAP121 (also known as AKAP1, or AKAP149 as the human homolog), with an emphasis on its role in mitochondrial physiology. AKAP121 has been identified to function as a key regulatory molecule in several mitochondrial events including oxidative phosphorylation, the control of membrane potential, fission-induced apoptosis, maintenance of mitochondrial Ca2+ homeostasis, and the phosphorylation of various mitochondrial respiratory chain substrate molecules. Furthermore, we discuss the role of hypoxia in prompting cellular stress and damage, which has been demonstrated to mediate the proteosomal degradation of AKAP121, leading to an increase in reactive oxgyen species production, mitochondrial dysfunction, and ultimately cell death.

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“…A fourfold reduction of AKAP149 gene expression was detected in adipose tissue of obese patients [95--97]. AKAP1 localizes predominantly type II PKA and other interaction partners to the outer mitochondrial membrane (reviewed in [98]). AKAP1 associates with mRNAs, e.g.…”

Section: Akaps In Glucose Homeostasis and Obesitymentioning

confidence: 99%

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

Deák¹,

Klussmann

2016

CDT

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A--kinase anchoring proteins (AKAPs) control the localization of cAMP--dependent protein kinase A (PKA) by tethering PKA to distinct cellular compartments. Through additional direct protein--protein interactions with PKA substrates and other signaling molecules they form multi--protein complexes. Thereby, AKAPs regulate the access of PKA to its substrates in a temporal and spatial manner as well as the local crosstalk of cAMP/PKA with other signaling pathways.Due to the increasing information on their molecular functioning and three--dimensional structures, and their emerging roles in the development of diseases, AKAPs move into the focus as potential drug targets. In particular, targeting AKAP--dependent protein--protein interactions for interference with local signal processing inside cells potentially allows for the development of therapeutics with high selectivity and fewer side effects.4

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Mitochondria: A kinase anchoring protein 1, a signaling platform for mitochondrial form and function

Cited by 91 publications

References 48 publications

GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis signaling in the regulation of mitochondrial elongation

GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis signaling in the regulation of mitochondrial elongation

Pivotal role of AKAP121 in mitochondrial physiology

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

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