Pseudoscaffolds and anchoring proteins: the difference is in the details

Aggarwal-Howarth, Stacey; Scott, John D.

doi:10.1042/bst20160329

Cited by 6 publications

(5 citation statements)

References 87 publications

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“…An important implication of this broader redefinition of allosteric drug target is that the response to a given stimulus by a given receptor may vary depending on subcellular localization and on the specific signalosome in which PKA is integrated. Subcellular localization and signalosomes dictate the effective local concentrations and types of substrates and metabolites to which PKA is exposed (36,37), potentially affecting pluripotent allostery.…”

Section: Metabolomic Proteomic and Genomic Triggers Of Pluripotent Al...mentioning

confidence: 99%

Allosteric pluripotency as revealed by protein kinase A

et al. 2020

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The functional response of a signaling system to an allosteric stimulus often depends on subcellular conditions, a phenomenon known as pluripotent allostery. For example, a single allosteric modulator, Rp-cAMPS, of the prototypical protein kinase A (PKA) switches from antagonist to agonist depending on MgATP levels. However, the mechanism underlying such pluripotent allostery has remained elusive for decades. Using nuclear magnetic resonance spectroscopy, ensemble models, kinase assays, and molecular dynamics simulations, we show that allosteric pluripotency arises from surprisingly divergent responses of highly homologous tandem domains. The differential responses perturb domain-domain interactions and remodel the free-energy landscape of inhibitory excited states sampled by the regulatory subunit of PKA. The resulting activation threshold values are comparable to the effective free energy of regulatory and catalytic subunit binding, which depends on metabolites, substrates, and mutations, explaining pluripotent allostery and warranting a general redefinition of allosteric targets to include specific subcellular environments.

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Section: Metabolomic Proteomic and Genomic Triggers Of Pluripotent Al...mentioning

confidence: 99%

Allosteric pluripotency as revealed by protein kinase A

et al. 2020

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“… Allosteric regulation of chromatin-modifying activities: pseudokinases can function as pseudoscaffolds modulating the availability of substrates to enzymes (reviewed in [82]).…”

Section: Perspectivesmentioning

confidence: 99%

New insights into the evolutionary conservation of the sole PIKK pseudokinase Tra1/TRRAP

Elías-Villalobos

Fort

Helmlinger

2019

Biochemical Society Transactions

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Phosphorylation by protein kinases is a fundamental mechanism of signal transduction. Many kinase families contain one or several members that, although evolutionarily conserved, lack the residues required for catalytic activity. Studies combining structural, biochemical, and functional approaches revealed that these pseudokinases have crucial roles in vivo and may even represent attractive targets for pharmacological intervention. Pseudokinases mediate signal transduction by a diversity of mechanisms, including allosteric regulation of their active counterparts, assembly of signaling hubs, or modulation of protein localization. One such pseudokinase, named Tra1 in yeast and transformation/transcription domain-associated protein (TRRAP) in mammals, is the only member lacking all catalytic residues within the phosphatidylinositol 3-kinase related kinase (PIKK) family of kinases. PIKKs are related to the PI3K family of lipid kinases, but function as Serine/Threonine protein kinases and have pivotal roles in diverse processes such as DNA damage sensing and repair, metabolic control of cell growth, nonsense-mediated decay, or transcription initiation. Tra1/TRRAP is the largest subunit of two distinct transcriptional co-activator complexes, SAGA and NuA4/TIP60, which it recruits to promoters upon transcription factor binding. Here, we review our current knowledge on the Tra1/TRRAP pseudokinase, focusing on its role as a scaffold for SAGA and NuA4/TIP60 complex assembly and recruitment to chromatin. We further discuss its evolutionary history within the PIKK family and highlight recent findings that reveal the importance of molecular chaperones in pseudokinase folding, function, and conservation.

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“…4 indicate that cell lines designated as dAKAP1-high display robust basal mitochondrial membrane potentials. This feature is often associated with enhanced oxidative phosphorylation, a metabolic process that exploits the transfer of electrons across inner mitochondrial membranes to promote ATP synthesis (40,62). Paradoxically these findings imply that although dAKAP1 signaling islands reside on the outer mitochondrial membrane, they somehow seem to influence metabolic processes that occur inside these organelles.…”

Section: Reduced Dakap1 Is Linked To Metastasismentioning

confidence: 99%

Depletion of dAKAP1–protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility

Aggarwal¹,

Gabrovsek²,

Langeberg

et al. 2019

Journal of Biological Chemistry

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Breast cancer screening and new precision therapies have led to improved patient outcomes. Yet, a positive prognosis is less certain when primary tumors metastasize. Metastasis requires a coordinated program of cellular changes that promote increased survival, migration, and energy consumption. These pathways converge on mitochondrial function, where distinct signaling networks of kinases, phosphatases, and metabolic enzymes regulate these processes. The protein kinase A-anchoring protein dAKAP1 compartmentalizes protein kinase A (PKA) and other signaling enzymes at the outer mitochondrial membrane and thereby controls mitochondrial function and dynamics. Modulation of these processes occurs in part through regulation of dynamin-related protein 1 (Drp1). Here, we report an inverse relationship between the expression of dAKAP1 and mesenchymal markers in breast cancer. Molecular, cellular, and in silico analyses of breast cancer cell lines confirmed that dAKAP1 depletion is associated with impaired mitochondrial function and dynamics, as well as with increased glycolytic potential and invasiveness. Furthermore, disruption of dAKAP1-PKA complexes affected cell motility and mitochondrial movement toward the leading edge in invasive breast cancer cells. We therefore propose that depletion of dAKAP1-PKA "signaling islands" from the outer mitochondrial membrane augments progression toward metastatic breast cancer. Approximately one in eight women are diagnosed with breast cancer. Recent advances in detection and diagnosis, when combined with precision therapies that tailor drug treatment to the genetic profile of patients increase the likelihood of good prognoses (1). Nonetheless, 5-year survival rates plummet to 22% for patients with metastatic (stage IV) disease (2). Elucidating the molecular mechanisms that underlie the transition to metastatic breast cancers remains challenging, yet it is a necessary prelude to the development of new therapies. The onset of metastasis is often marked by a cellular reprogramming paradigm that alters gene expression patterns, migration competency, and metabolism (3). This paradigm shares many features with the developmental process known as the epithelial-to-mesenchymal transition (EMT) 6 (4-6). Furthermore, highly proliferative cancer cells often exhibit enhanced glycolytic capacity (3, 7). Recent studies show that both glycolysis and oxidative metabolism at mitochondria are critical for the progression to metastasis and the survival of cancer cells as they establish distant tumors (8-10). Such multifaceted control of tumor cell metabolism highlights the importance of mitochondrial signaling events during metastatic tumor progression. Bioinformatic analyses of mRNA and protein data sets have identified predictive elements of tumor progression that change during EMT and metastasis (11, 12). Many of these altered proteins regulate processes such as cytoskeletal remodeling, cell adhesion, and cellular metabolism, which are critical to tumor cell migration and survival (11). One class of...

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Pseudoscaffolds and anchoring proteins: the difference is in the details

Cited by 6 publications

References 87 publications

Allosteric pluripotency as revealed by protein kinase A

Allosteric pluripotency as revealed by protein kinase A

New insights into the evolutionary conservation of the sole PIKK pseudokinase Tra1/TRRAP

Depletion of dAKAP1–protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility

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