Association of Tyrosine-phosphorylated c-Src with the Cytoskeleton of Hypertrophying Myocardium

Kuppuswamy, Dhandapani; Kerr, Charlene M.; Narishige, Takahiro; Kasi, Vijaykumar S.; Menick, Donald R.; Cooper, George

doi:10.1074/jbc.272.7.4500

Cited by 122 publications

(140 citation statements)

References 43 publications

Supporting

Mentioning

129

Contrasting

Order By: Relevance

“…Differences do exist, because activation of FAK occurs predominantly via integrin engagement (38,39), pyk2/RAFTK cannot fully compensate for loss FAK (21), and functional roles for pyk2/RAFTK and FAK are markedly distinct under certain conditions (40,41). Participation of FAK in cardiovascular signaling occurs in cardiomyocytes responding to hypoxia (42), pulsatile stretch (43,44), vascular endothelial growth factor (45), and hypertrophy in vivo (46,47) and in vitro (48 -51). 402 .…”

Section: Discussionmentioning

confidence: 99%

Activation of pyk2/Related Focal Adhesion Tyrosine Kinase and Focal Adhesion Kinase in Cardiac Remodeling

Meléndez

Welch

Schaefer³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cellular remodeling during progression of dilation involves focal adhesion contact reorganization. However, the signaling mechanisms and structural consequences leading to impaired cardiomyocyte adhesion are poorly defined. These events were studied in tropomodulinoverexpressing transgenic mice that develop dilated cardiomyopathy associated with chronic elevation of intracellular calcium. Analysis of tropomodulin-overexpressing transgenic hearts by immunoblot and confocal microscopy revealed activation and redistribution of signaling molecules known to regulate adhesion. Calcium-dependent pyk2/related focal adhesion tyrosine kinase (RAFTK) showed changes in expression and phosphorylation state, similar to changes observed for a related downstream target molecule of pyk2/RAFTK termed focal adhesion kinase. Paxillin, the target substrate molecule for focal adhesion kinase phosphorylation, was redistributed in tropomodulin-overexpressing transgenic hearts with enhanced paxillin phosphorylation and cleavage. Certain aspects of the in vivo signaling phenotype including increased paxillin phosphorylation could be recapitulated in vitro using neonatal rat cardiomyocytes infected with recombinant adenovirus to overexpress tropomodulin. In addition, increasing intracellular calcium levels with ionomycin induced pyk2/ RAFTK phosphorylation, and adenovirally mediated expression of wild-type pyk2/RAFTK resulted in increased phospho-pyk2/RAFTK levels and concomitant paxillin phosphorylation. Collectively, these results delineate a cardiomyocyte signaling pathway associated with dilation that has potential relevance for cardiac remodeling, focal adhesion reorganization, and loss of contractility.Altered intracellular calcium handling is characteristic of heart failure, presumably as a compensatory mechanism to stimulate contractile function and signal transduction (1, 2). Chronic elevation of diastolic calcium level consequently activates calcium-dependent signal transduction pathways. Calcium-activated pathways regulate cardiac function, and disruption of calcium-responsive signaling has been associated with cardiomyopathic changes in experimental transgenic mouse models. Myocardium-specific transgenic overexpression of calcium-activated enzymes such as protein kinase C ␤2 (3, 4) or calcineurin (5) cause hypertrophy. Calcineurin activation, hypertrophic remodeling, and elevation of intracellular calcium are associated with heart failure in a cardiomyopathic transgenic mouse model created by overexpression of tropomodulin (Tmod), 1 a regulatory component of the sarcomere (6). Tmodoverexpressing transgenic (TOT) hearts are characterized by a combination of increased intracellular calcium levels, myofibril degeneration, loss of systolic function, and inability to hypertrophy. This constellation of features is reminiscent of degenerative changes associated with heart failure (1, 7, 8), making the TOT mouse a useful model for studying structural and signaling changes occurring in myocardial decompensation.TOT hearts dilate rapidl...

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of pyk2/Related Focal Adhesion Tyrosine Kinase and Focal Adhesion Kinase in Cardiac Remodeling

Meléndez

Welch

Schaefer³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…10 The TSS was further separated into cytoplasmic (CF) and membrane skeleton fractions (MSFs) as described. 4 The extraction of nuclear protein (NP) was performed as described. 12 An equal amount of total protein, determined with the Bio-Rad Coomassie protein assay (Bio-Rad Laboratories), was loaded and run on 10% Laemmli sodium dodecyl sulfate-polyacrylamide gel as described.…”

Section: Antigen Retrievalmentioning

confidence: 99%

Subcellular Redistribution of Focal Adhesion Kinase and Its Related Nonkinase in Hypertrophic Myocardium

Wang

Gerdes

et al. 2003

Hypertension

View full text Add to dashboard Cite

Abstract-Focal adhesion kinase (FAK) and focal adhesion kinase-related nonkinase (FRNK) are likely involved in mechanical signaling during hypertension. We investigated expression, subcellular distribution, and phosphorylation of FAK, as well as FRNK in left ventricles of spontaneously hypertensive heart failure rats. Key Words: hypertrophy Ⅲ heart failure Ⅲ kinase Ⅲ cell signaling O ur studies on lean female spontaneously hypertensive heart failure (SHHF) rats 1 have shown that myocyte cross-sectional growth responsible for ventricular wall thickening reaches a maximum at Ϸ4 months of age and remains stable thereafter. Myocyte lengthening, which underlies ventricular chamber dilatation, begins at 6 months of age and continues progressively with aging until the rats develop congestive heart failure (CHF) at 22 to 24 months of age. The switch from cross-sectional growth to myocyte lengthening Ϸ6 months in SHHF rats suggests that maladaptive remodeling and abnormal growth of cardiac myocytes begins long before overt cardiac decompensation. Therefore, the key to decipher the molecular mechanisms involved in the transition of concentric cardiac hypertrophy to maladaptive remodeling is to determine the signaling molecules that control series sarcomere assembly in cardiac myocytes.Focal adhesion kinase (FAK) is activated in cardiac myocytes and fibroblasts by in vitro treatment with a variety of hypertrophic stimuli. 2,3 The C-terminus of FAK is expressed as a separate protein known as focal adhesion kinase-related nonkinase (FRNK) in certain cell types. FRNK inhibits FAK tyrosine phosphorylation and endothelin-induced cardiac myocyte hypertrophy. 2 Recent studies have also shown that FAK is phosphorylated and activated during cardiac hypertrophy after acute pressure overload. 4 -6 The phosphorylation and activation of FAK appears to be transient and returns to normal levels after 1 week of overload. Thus, the potential role of FAK and FRNK in continuous remodeling of cardiac myocytes caused by chronic hypertension remains to be defined. FAK and FRNK may play a key role in cytoskeletal remodeling and maladaptive shape change of cardiac myocytes in SHHF rats.Serine phosphorylation of FAK and FRNK follows FAK tyrosine phosphorylation. 7 FAK become prominently phosphorylated on serine residues in a mitosis-specific fashion. 8 Serines 722 and 910 are 2 major serine phosphorylation sites of FAK in interphase cells. 7 The exact roles of these serine phosphorylation in mechanical signal transduction and cardiac hypertrophy remain to be investigated.In the present study, we examined expression and relationship between subcellular localization and phosphorylation of FAK and of FRNK in the left ventricles (LVs) of SHHF rats. Our results indicate that FAK is increased and translocated to membrane cytoskeleton, intercalated disks, and nuclei during cardiac hypertrophy in SHHF rats. The nuclear translocation of integrin-mediated signaling molecules may play an important role in regulating mechanical signal transduction to the nuc...

show abstract

“…Nonreceptor tyrosine kinases (29), Ras (20,23,30), Raf (31), MAPK (23, 27, 30 -33), SAPK (28), protein kinase C and Rsk (23,30) have each been implicated in signaling one or more components of the hypertrophic phenotype; however, no consensus exists as to which of these plays the dominant role in triggering the growth response. MAPK, for example, is known to be activated by both the biochemical agonists of hypertrophy as well as mechanical strain (23, 27, 30 -32), and dominant-negative mutants of MAPK and MAPK kinase (MEK), which lies immediately upstream from MAPK in the effector cascade (34), suppress phenylephrine induction of a transiently transfected rat ANP promoter (31).…”

mentioning

confidence: 99%

Mechanical Strain Increases Expression of the Brain Natriuretic Peptide Gene in Rat Cardiac Myocytes

Liang

Garami³

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

Using a device that applies cyclical strain (1 Hz) to ventricular cardiocytes cultured on collagen-coated silicone elastomer surfaces, we have demonstrated straindependent increases in brain natriuretic peptide (BNP) secretion, BNP mRNA levels, and expression of a transiently transfected ؊1595 human BNP-luciferase reporter. When actinomycin D (10 M) was introduced concomitantly with the strain stimulus, the strain-induced increase in BNP mRNA was eliminated, and the decay of transcripts was identical in the control and strained cells, indicating the lack of independent effects on transcript stability. Strain-dependent ؊1595 human BNPluciferase activity was completely inhibited by chelerythrine, 2-aminopurine, genistein, and W-7 and only partially or not at all by KN-62, wortmannin, and H-89. The effects of these individual agents paralleled their effects on mitogen-activated protein kinase (MAPK) activity, but not c-Jun N-terminal kinase (JNK) activity, in the cells. Overexpression of wild-type MAPK and, to a lesser extent, JNK increased strain-dependent BNP promoter activity, whereas dominant-negative mutants of MAPK kinase, JNK kinase, or Ras completely blocked strain-dependent reporter activity. These findings provide the first demonstration that mechanical strain can increase myocardial gene expression through a transcriptional mechanism and suggest important roles for MAPK and JNK in mediating this effect.The natriuretic peptides comprise a family of vasoactive hormones that play an important role in the regulation of cardiovascular and renal homeostasis (1). Their natriuretic and vasodepressor properties suggest that they represent endogenous antagonists of the various systems (e.g. renin-angiotensin system and sympathetic nervous system) that support arterial blood pressure under basal conditions and, at times, contribute to the pathophysiology of cardiovascular disease.Atrial natriuretic peptide (ANP), 1 the prototype of the group, is produced primarily in the atria of the heart. ANP is expressed in the cardiac ventricle during development and early neonatal life (2, 3). Expression decays as the animal ages and remains quiescent in the adult unless the ventricle is subjected to hemodynamic overload (i.e. mechanical strain that leads to increased wall stress and subsequently to hypertrophy of the myocardium), as occurs with systemic arterial hypertension or congestive heart failure (4 -7).Brain natriuretic peptide (BNP) is also produced in the heart. Despite the nomenclature, relatively little BNP is expressed in the mammalian brain (the exception being the porcine brain, where the peptide was identified originally). Expression of BNP in the heart is lower than that of ANP under basal conditions, and the atrial/ventricular ratio of expression is considerably less than that seen with ANP (8). Ventricular expression of BNP is activated in a fashion similar to ANP in pathophysiological states associated with hemodynamic overload (9, 10). At some stages of advanced congestive heart failure, circulating BNP le...

show abstract

Association of Tyrosine-phosphorylated c-Src with the Cytoskeleton of Hypertrophying Myocardium

Cited by 122 publications

References 43 publications

Activation of pyk2/Related Focal Adhesion Tyrosine Kinase and Focal Adhesion Kinase in Cardiac Remodeling

Activation of pyk2/Related Focal Adhesion Tyrosine Kinase and Focal Adhesion Kinase in Cardiac Remodeling

Subcellular Redistribution of Focal Adhesion Kinase and Its Related Nonkinase in Hypertrophic Myocardium

Mechanical Strain Increases Expression of the Brain Natriuretic Peptide Gene in Rat Cardiac Myocytes

Contact Info

Product

Resources

About