p21-Activated Kinase Increases the Calcium Sensitivity of Rat Triton-Skinned Cardiac Muscle Fiber Bundles via a Mechanism Potentially Involving Novel Phosphorylation of Troponin I

Buscemi, Nina; Foster, D. Brian; Neverova, Irina; Eyk, Jennifer E. Van

doi:10.1161/01.res.0000035246.27856.53

Cited by 82 publications

(75 citation statements)

References 37 publications

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“…In contrast, the functional effects of phosphorylating cTnI Ser149 have not been well characterized but evidence suggests that phosphorylation of this site may be associated with an increase in the Ca 2þ sensitivity of the myofilaments. 25,52 Another signaling enzyme, PAK has been shown to phosphorylate cTnI at Ser149. 25 PAK is a serine/threonine protein kinase expressed in most mammalian tissues and activated by the small GTPases Cdc42 and Rac1.…”

Section: Physiological Implications Of Phosphorylation At Ser22ser23 mentioning

confidence: 99%

“…25,52 Another signaling enzyme, PAK has been shown to phosphorylate cTnI at Ser149. 25 PAK is a serine/threonine protein kinase expressed in most mammalian tissues and activated by the small GTPases Cdc42 and Rac1. 53 Several isoforms have been described, including PAK1, PAK2, and PAK3, with PAK1 being the major isoform expressed in the heart.…”

Section: Physiological Implications Of Phosphorylation At Ser22ser23 mentioning

confidence: 99%

“…53 Several isoforms have been described, including PAK1, PAK2, and PAK3, with PAK1 being the major isoform expressed in the heart. 54 Buscemi et al 25 found that phosphorylation of cTnI Ser149 by PAK3 was accompanied by an increase in the Ca 2þ sensitivity of myofilament force development. A study by Ke et al 55 found that, although PAK1 could phosphorylate cTnI in vitro, adenovirus infection of isolated myocytes with a constitutively active PAK1 construct decreased the overall phosphorylation status of cTnI and increased the Ca 2þ sensitivity of force production.…”

Section: Physiological Implications Of Phosphorylation At Ser22ser23 mentioning

confidence: 99%

“…15 cTnI and other myofilament proteins are also targeted by additional protein kinases involved in signaling such as protein kinase C (PKC), [17][18][19][20][21][22] protein kinase D (PKD), 23,24 and p21-activated kinase (PAK). 25 For example, PKC is able to phosphorylate cTnI at Ser41, Ser43, and Thr142 (human cTnI sequence excluding the initial methionine), although it can also cross-phosphorylate the PKA sites, albeit slowly. 18,19 Phosphorylation of each of these sites on cTnI has been associated with functional changes, 15 although the precise assignment of a specific altered function to the phosphorylation of a specific site has proven difficult.…”

Section: Introductionmentioning

confidence: 99%

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A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

Solis

Walker

2011

Protein Science

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5 0 -AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that is activated when cellular AMP to ATP ratios rise, potentially serving as a key regulator of cellular energetics. Among the known targets of AMPK are catabolic and anabolic enzymes, but little is known about the ability of this kinase to phosphorylate myofilament proteins and thereby regulating the contractile apparatus of striated muscles. Here, we demonstrate that troponin I isoforms of cardiac (cTnI) and fast skeletal (fsTnI) muscles are readily phosphorylated by AMPK. For cTnI, two highly conserved serine residues were identified as AMPK sites using a combination of high-resolution top-down electron capture dissociation mass spectrometry, 32 P-incorporation, synthetic peptides, phospho-specific antibodies, and site-directed mutagenesis. These AMPK sites in cTnI were Ser149 adjacent to the inhibitory loop and Ser22 in the cardiac-specific N-terminal extension, at the level of cTnI peptides, the intact cTnI subunit, whole cardiac troponin complexes and skinned cardiomyocytes. Phosphorylation time-course experiments revealed that Ser149 was the preferred site, because it was phosphorylated 12-16-fold faster than Ser22 in cTnI. Ser117 in fsTnI, analogous to Ser149 in cTnI, was phosphorylated with similar kinetics as cTnI Ser149. Hence, the master energy-sensing protein AMPK emerges as a possibly important regulator of cardiac and skeletal contractility via phosphorylation of a preferred site adjacent to the inhibitory loop of the thin filament protein TnI.

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Section: Physiological Implications Of Phosphorylation At Ser22ser23 mentioning

confidence: 99%

Section: Physiological Implications Of Phosphorylation At Ser22ser23 mentioning

confidence: 99%

Section: Physiological Implications Of Phosphorylation At Ser22ser23 mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

Solis

Walker

2011

Protein Science

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“…Khodarev et al, (2001) showed that modulation of cytoskeleton genes including troponin T1 was induced by irradiation at dose of 1, 3 or 10 Gy in a human malignant gliomas cell line. In addition, PAK3, a GTPase-dependent kinase involved in multiple signaling pathways including axonal guidance signaling, directly interacts with the troponin T complex (Buscemi et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Molecular stress response in the CNS of mice after systemic exposure to interferon-α, ionizing radiation and ketamine

et al. 2009

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We previously showed that the expression of troponin T1 (Tnnt 1) was induced in the central nervous system (CNS) of adult mice 30 minutes after treatment with ketamine, a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist. We hypothesized that Tnnt 1 expression may be an early molecular biomarker of stress response in the CNS of mice. To further evaluate this hypothesis, we investigated the regional expression of Tnnt

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Proteomic changes in hearts of kyphoscoliosis (ky) mutant mice in the absence of structural pathology: Implication for the analysis of early human heart disease

Hou¹,

Bihan²,

Vega‐Avelaira³

et al. 2006

Proteomics

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Complex molecular changes associated with early stage human heart disease are poorly understood and prevent the development of effective treatments of human cardiac disease. Relatively minor structural changes in early disease may accompany some conditions such as arrhythmias. Our objective was to determine if significant proteomic changes occur in heart tissues in the absence of structural pathology. We used a proteomic "pipeline" based on Ciphergen SELDI-TOF/MS, gel electrophoresis and MALDI-TOF/MS. The kyphoscoliosis (ky) mouse carries a mutation in a putative transglutaminase causing a primary skeletal muscle disease. The ky protein is expressed usually in skeletal and cardiac muscle but its absence from the ky heart causes no structural pathology making it a good model of "occult" heart disease. We discovered 20 statistically validated biomarkers discriminating ky from normal hearts, one cardiac troponin-I was reduced by 40% in ky hearts. A 17% deficit was confirmed subsequently by Western blot. Thus, the proteome of ky hearts was abnormal, giving support to our contention that this SELDI-based analytical approach is capable of making a significant contribution to the analysis of complex proteomic changes in early stage human heart disease.

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p21-Activated Kinase Increases the Calcium Sensitivity of Rat Triton-Skinned Cardiac Muscle Fiber Bundles via a Mechanism Potentially Involving Novel Phosphorylation of Troponin I

Cited by 82 publications

References 37 publications

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

Molecular stress response in the CNS of mice after systemic exposure to interferon-α, ionizing radiation and ketamine

Proteomic changes in hearts of kyphoscoliosis (ky) mutant mice in the absence of structural pathology: Implication for the analysis of early human heart disease

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