Darren E. Casteel
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View article: A plasma membrane–associated form of the androgen receptor enhances nuclear androgen signaling in osteoblasts and prostate cancer cells
A plasma membrane–associated form of the androgen receptor enhances nuclear androgen signaling in osteoblasts and prostate cancer cells Open
Androgen binding to the androgen receptor (AR) in the cytoplasm induces the AR to translocate to the nucleus, where it regulates the expression of target genes. Here, we found that androgens rapidly activated a plasma membrane–associated s…
View article: The Antioxidant/Nitric Oxide-Quenching Agent Cobinamide Prevents Aortic Disease in a Mouse Model of Marfan Syndrome
The Antioxidant/Nitric Oxide-Quenching Agent Cobinamide Prevents Aortic Disease in a Mouse Model of Marfan Syndrome Open
Major pathologic changes in the proximal aorta underlie the life-threatening aortic aneurysms and dissections in Marfan Syndrome; current treatments delay aneurysm development without addressing the primary pathology. Because excess oxidat…
View article: Phosphatase regulatory subunit MYPT2 knockout partially compensates for the cardiac dysfunction in mice caused by lack of myosin light chain kinase 3
Phosphatase regulatory subunit MYPT2 knockout partially compensates for the cardiac dysfunction in mice caused by lack of myosin light chain kinase 3 Open
View article: Cobinamide is a strong and versatile antioxidant that overcomes oxidative stress in cells, flies, and diabetic mice
Cobinamide is a strong and versatile antioxidant that overcomes oxidative stress in cells, flies, and diabetic mice Open
Increased oxidative stress underlies a variety of diseases, including diabetes. Here, we show that the cobalamin/vitamin B12 analog cobinamide is a strong and multifaceted antioxidant, neutralizing superoxide, hydrogen peroxide, and peroxy…
View article: An auto-inhibited state of protein kinase G and implications for selective activation
An auto-inhibited state of protein kinase G and implications for selective activation Open
Cyclic GMP-dependent protein kinases (PKGs) are key mediators of the nitric oxide/cyclic guanosine monophosphate (cGMP) signaling pathway that regulates biological functions as diverse as smooth muscle contraction, cardiac function, and ax…
View article: Author response: An auto-inhibited state of protein kinase G and implications for selective activation
Author response: An auto-inhibited state of protein kinase G and implications for selective activation Open
Article Figures and data Abstract Editor's evaluation Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Cyclic GMP-dependent p…
View article: PKGIα is activated by metal-dependent oxidation in vitro but not in intact cells
PKGIα is activated by metal-dependent oxidation in vitro but not in intact cells Open
Type I cGMP-dependent protein kinases (PKGIs) are important components of various signaling pathways and are canonically activated by nitric oxide- and natriuretic peptide-induced cGMP generation. However, some reports have shown that PKGI…
View article: An auto-inhibited state of protein kinase G and implications for selective activation
An auto-inhibited state of protein kinase G and implications for selective activation Open
Cyclic GMP-dependent protein kinases (PKGs) are key mediators of the nitric oxide/cGMP signaling pathway that regulates biological functions as diverse as smooth muscle contraction, cardiac function, and axon guidance. Campaigns targeting …
View article: Bladder Cancer Invasion Is Mediated by Mammalian Target of Rapamycin Complex 2–Driven Regulation of Nitric Oxide and Invadopodia Formation
Bladder Cancer Invasion Is Mediated by Mammalian Target of Rapamycin Complex 2–Driven Regulation of Nitric Oxide and Invadopodia Formation Open
View article: Constitutive protein kinase G activation exacerbates stress‐induced cardiomyopathy
Constitutive protein kinase G activation exacerbates stress‐induced cardiomyopathy Open
Background and Purpose Heart failure is associated with high morbidity and mortality, and new therapeutic targets are needed. Preclinical data suggest that pharmacological activation of protein kinase G (PKG) can reduce maladaptive ventric…
View article: Ncor2/PPARα-dependent upregulation of MCUb in the type 2 diabetic heart impacts cardiac metabolic flexibility and function
Ncor2/PPARα-dependent upregulation of MCUb in the type 2 diabetic heart impacts cardiac metabolic flexibility and function Open
The contribution of altered mitochondrial Ca2+ handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. Here, we show that the T2D heart is metabolically inflexible and almost ex…
View article: Ncor2/PPARα-Dependent Upregulation of MCUb in the Type 2 Diabetic Heart Impacts Cardiac Metabolic Flexibility and Function
Ncor2/PPARα-Dependent Upregulation of MCUb in the Type 2 Diabetic Heart Impacts Cardiac Metabolic Flexibility and Function Open
The contribution of altered mitochondrial Ca2+ handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. In this study, we show that the T2D heart is metabolically inflexible and almost excl…
View article: Ncor2/PPARα-dependent upregulation of MCUb in the type 2 diabetic heart impacts cardiac metabolic flexibility and function
Ncor2/PPARα-dependent upregulation of MCUb in the type 2 diabetic heart impacts cardiac metabolic flexibility and function Open
The contribution of altered mitochondrial Ca2+ handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. Here, we show that the T2D heart is metabolically inflexible and almost ex…
View article: Protein Kinase G2 Is Essential for Skeletal Homeostasis and Adaptation to Mechanical Loading in Male but Not Female Mice
Protein Kinase G2 Is Essential for Skeletal Homeostasis and Adaptation to Mechanical Loading in Male but Not Female Mice Open
We previously showed that the NO/cGMP/protein kinase G (PKG) signaling pathway positively regulates osteoblast proliferation, differentiation, and survival in vitro, and that cGMP-elevating agents have bone-anabolic effects in mice. Here, …
View article: Metabolic interaction between amino acid deprivation and cisplatin synergistically reduces phosphoribosyl-pyrophosphate and augments cisplatin cytotoxicity
Metabolic interaction between amino acid deprivation and cisplatin synergistically reduces phosphoribosyl-pyrophosphate and augments cisplatin cytotoxicity Open
Cisplatin is a mainstay of cancer chemotherapy. It forms DNA adducts, thereby activating poly(ADP-ribose) polymerases (PARPs) to initiate DNA repair. The PARP substrate NAD + is synthesized from 5-phosphoribose-1-pyrophosphate (PRPP), and …
View article: A substitution in cGMP-dependent protein kinase 1 associated with aortic disease induces an active conformation in the absence of cGMP
A substitution in cGMP-dependent protein kinase 1 associated with aortic disease induces an active conformation in the absence of cGMP Open
View article: Correction to: Crystal structure of PKG Iβ holoenzyme reveals a trans‑inhibiting dimer assembly
Correction to: Crystal structure of PKG Iβ holoenzyme reveals a trans‑inhibiting dimer assembly Open
After publication of abstract S 2‑06 in supplement [1], it was brought to our attention that the second author’s name is spelled incorrectly. Originally the author name has been published as Rajesh Sarma. The correct author name is Rajesh …
View article: Letter by Casteel Regarding Article, “Blood Pressure-Lowering by the Antioxidant Resveratrol Is Counterintuitively Mediated by Oxidation of the cGMP-Dependent Protein Kinase”
Letter by Casteel Regarding Article, “Blood Pressure-Lowering by the Antioxidant Resveratrol Is Counterintuitively Mediated by Oxidation of the cGMP-Dependent Protein Kinase” Open
View article: Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B12 analog
Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B12 analog Open
People heterozygous for an activating mutation in protein kinase G1 ( PRKG1 , p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice heterozygous for the mutation have a three-fold i…
View article: cGMP-dependent protein kinase-2 regulates bone mass and prevents diabetic bone loss
cGMP-dependent protein kinase-2 regulates bone mass and prevents diabetic bone loss Open
NO/cGMP signaling is important for bone remodeling in response to mechanical and hormonal stimuli, but the downstream mediator(s) regulating skeletal homeostasis are incompletely defined. We generated transgenic mice expressing a partly-ac…
View article: Structural basis for selective inhibition of human PKG Iα by the balanol-like compound N46
Structural basis for selective inhibition of human PKG Iα by the balanol-like compound N46 Open
Activation of protein kinase G (PKG) Iα in nociceptive neurons induces long-term hyperexcitability that causes chronic pain. Recently, a derivative of the fungal metabolite balanol, N46, has been reported to inhibit PKG Iα with high potenc…
View article: Phosphorylation of protein kinase A (PKA) regulatory subunit RIα by protein kinase G (PKG) primes PKA for catalytic activity in cells
Phosphorylation of protein kinase A (PKA) regulatory subunit RIα by protein kinase G (PKG) primes PKA for catalytic activity in cells Open
View article: Protein Kinase G Activation Reverses Oxidative Stress and Restores Osteoblast Function and Bone Formation in Male Mice With Type 1 Diabetes
Protein Kinase G Activation Reverses Oxidative Stress and Restores Osteoblast Function and Bone Formation in Male Mice With Type 1 Diabetes Open
Bone loss and fractures are underrecognized complications of type 1 diabetes and are primarily due to impaired bone formation by osteoblasts. The mechanisms leading to osteoblast dysfunction in diabetes are incompletely understood, but ins…
View article: The activity of cGMP-dependent protein kinase Iα is not directly regulated by oxidation-induced disulfide formation at cysteine 43
The activity of cGMP-dependent protein kinase Iα is not directly regulated by oxidation-induced disulfide formation at cysteine 43 Open
View article: Argininosuccinate Synthetase 1 Loss in Invasive Bladder Cancer Regulates Survival through General Control Nonderepressible 2 Kinase–Mediated Eukaryotic Initiation Factor 2α Activity and Is Targetable by Pegylated Arginine Deiminase
Argininosuccinate Synthetase 1 Loss in Invasive Bladder Cancer Regulates Survival through General Control Nonderepressible 2 Kinase–Mediated Eukaryotic Initiation Factor 2α Activity and Is Targetable by Pegylated Arginine Deiminase Open
View article: O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts
O-GlcNAcylation of 8-Oxoguanine DNA Glycosylase (Ogg1) Impairs Oxidative Mitochondrial DNA Lesion Repair in Diabetic Hearts Open
mtDNA damage in cardiac myocytes resulting from increased oxidative stress is emerging as an important factor in the pathogenesis of diabetic cardiomyopathy. A prevalent lesion that occurs in mtDNA damage is the formation of 8-hydroxy-2'-d…
View article: AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2
AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2 Open
K-Ras must localize to the plasma membrane and be arrayed in nanoclusters for biological activity. We show here that K-Ras is a substrate for cyclic GMP-dependent protein kinases (PKGs). In intact cells, activated PKG2 selectively colocali…
View article: A Novel, Direct NO Donor Regulates Osteoblast and Osteoclast Functions and Increases Bone Mass in Ovariectomized Mice
A Novel, Direct NO Donor Regulates Osteoblast and Osteoclast Functions and Increases Bone Mass in Ovariectomized Mice Open
Most US Food and Drug Administration (FDA)-approved treatments for osteoporosis target osteoclastic bone resorption. Only PTH derivatives improve bone formation, but they have drawbacks, and novel bone-anabolic agents are needed. Nitrates,…
View article: Crystal Structure of PKG I:cGMP Complex Reveals a cGMP-Mediated Dimeric Interface that Facilitates cGMP-Induced Activation
Crystal Structure of PKG I:cGMP Complex Reveals a cGMP-Mediated Dimeric Interface that Facilitates cGMP-Induced Activation Open
View article: Structural Basis of Cyclic Nucleotide Selectivity in cGMP-dependent Protein Kinase II
Structural Basis of Cyclic Nucleotide Selectivity in cGMP-dependent Protein Kinase II Open