p38 Mitogen-activated protein kinase  expression and activation in smooth muscle

Hedges, Jason C.; Yamboliev, Ilia A.; Ngo, Mai Huong T.; Horowitz, Burton; Adam, Leonard P.; Gerthoffer, William T.

doi:10.1152/ajpcell.1998.275.2.c527

Cited by 66 publications

(45 citation statements)

References 26 publications

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“…In addition, the mechanisms of p38MAPK activation differed between agonists, with NA having a requirement for calcium but not herbimycin A-sensitive tyrosine kinases and with ET-1 being partially dependent on extracellular calcium and tyrosine kinases. Identification of 4 p38MAPK isoforms in rat mesenteric small arteries confirms and extends the observations of Hedges et al, 19 who identified p38␣ in canine smooth muscle. The present study shows GPCR activation of p38␣ and/or p38␤ isoforms in smooth muscle, with no detectable activation of the SAPK3/p38␥ or SAPK4/p38␦ isoforms.…”

Section: Discussionsupporting

confidence: 87%

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Activation of p38 Mitogen-Activated Protein Kinases by Endothelin and Noradrenaline in Small Arteries, Regulation by Calcium Influx and Tyrosine Kinases, and Their Role in Contraction

Ohanian

Cunliffe

Ceppi

et al. 2001

ATVB

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Abstract-Small-artery responses to vasoconstrictor agonists are important for vascular function. To investigate the signaling pathways involved in contraction, we studied the activation and regulation of p38 mitogen-activated protein kinases (p38MAPKs) and heat shock protein (HSP) kinase by endothelin and noradrenaline in rat mesenteric arteries. Both vasoconstrictors activated p38␣ and/or p38␤ but not p38␥ or p38␦, leading to increased HSP kinase activity. p38MAPK activation by noradrenaline was maximum between 2 and 10 minutes and was wholly dependent on calcium influx but insensitive to the tyrosine kinase inhibitor herbimycin A. In contrast, endothelin induced a biphasic response, with activation at 2 and 10 minutes. The early activity was wholly dependent on calcium influx and inhibited by herbimycin A. The later activity was only 50% calcium dependent, was insensitive to herbimycin A, but was 50% inhibited by genistein, a nonselective tyrosine kinase inhibitor. With both agonists, p38MAPK activity returned to basal by 30 minutes. SB203580, a p38MAPK inhibitor, blocked agonist-induced HSP kinase activity, and herbimycin A inhibited activation by endothelin but not by noradrenaline. In addition, SB203580 inhibited noradrenaline-induced contraction but had little effect on contraction to endothelin. These data show that vasoconstrictors use different upstream activators of p38MAPK in vascular tissue and that the p38MAPK pathway is selectively implicated in the contractile response to noradrenaline in small arteries. Key Words: vasoconstrictors Ⅲ vascular smooth muscle Ⅲ heat shock proteins Ⅲ signal transduction V ascular tone is an important determinant of peripheral resistance and blood pressure, and abnormalities in small-artery contractility contribute to pathological states such as vasospasm and hypertension. 1 The major mechanism of smooth muscle contraction is an increase in cytoplasmic calcium and phosphorylation of the regulatory light chains of myosin. However, there is considerable evidence indicating that vasoconstrictors activate multiple ancillary pathways that modulate the contractile response (see reviews 2,3 ). Among the many pathways activated, protein kinase C, 2 Rho family G proteins, 3,4 nonreceptor tyrosine kinases, 5 and extracellular signal-regulated kinases (ERK1/2) 2,6 have been shown to play a role in smooth muscle contraction. Recently, stressactivated protein kinases have also been implicated in sustained contraction through regulation of the phosphorylation of heat shock protein (HSP) 27. 7 HSP27 belongs to a family of small HSPs that includes HSP20, myotonic dystrophy kinase-binding proteins, and crystallins. 8 Increased phosphorylation of HSP27 has been reported in response to a variety of vasoconstrictors in smooth muscle, 9 -12 and inhibition of HSP27 phosphorylation or interference with its function reduces contraction. 9 HSPs may also play a role in vascular diseases such as hypertension. For instance, stress-induced hypertension in rats increased the expression and phos...

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Section: Discussionsupporting

confidence: 87%

“…The p38␣/␤ band had an apparent molecular mass of 41 kDa, in agreement with canine smooth muscle p38MAPK. 19 The molecular mass of SAPK3 (p38␥) and SAPK4 (p38␦) was Ϸ39 kDa. …”

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confidence: 97%

Activation of p38 Mitogen-Activated Protein Kinases by Endothelin and Noradrenaline in Small Arteries, Regulation by Calcium Influx and Tyrosine Kinases, and Their Role in Contraction

Ohanian

Cunliffe

Ceppi

et al. 2001

ATVB

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“…Recent publications showed that bradykinin and thromboxane A 2 activate MAPK pathways via PKC-dependent G i ␣ protein coupling in human cells (20,29). In addition, PKC may increase the contractility of the airway smooth muscle by inhibiting caldesmon (via the MAPK pathways) and calponin (directly), which are involved in modulation of the actin-myosin interaction (30,61). We show here that blockage of PKC by calphostin C effectively inhibits fenoterol-induced sensitization.…”

Section: Discussionmentioning

confidence: 55%

“…Recent studies underline the role of the MAPK in the intracellular processes of airway smooth muscle proliferation and sensitization (2,30,32,46,58,61 (12,23,32,53). Moreover, MAPK increases the G i protein activity, which results in a functional uncoupling between G s protein and ␤ 2 -adrenoceptor (2,32,37).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, MAPK increases the G i protein activity, which results in a functional uncoupling between G s protein and ␤ 2 -adrenoceptor (2,32,37). In addition, MAPK enhances the myosin light chain kinase activity and the heavy chain of myosin expression (32) and may increase smooth muscle contraction probably via h-caldesmon phosphorylation and actin-F remodeling (30). Interestingly, prostanoids such as thromboxane A 2 stimulate the MAPK by coupling the TP receptor with G␣ q (activation of PKC) or G i ␤␥ proteins (2,32,34), and leukotrienes increase the MAPK expression in humans (48,49).…”

Section: Discussionmentioning

confidence: 99%

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In vitro sensitization of human bronchus by β₂-adrenergic agonists

Faisy¹,

Naline²,

Diehl

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Ϫ7 M fenoterol induced sensitization characterized by an increase in maximal contraction to endothelin-1 (ET-1) and acetylcholine (ACh). Incubation of human bronchi with 10 Ϫ6 , 3 ϫ 10 Ϫ6 , and 10 Ϫ5 M forskolin (an adenyl cyclase activator) reproduced sensitization to ET-1 and ACh. The sensitizing effect of fenoterol was inhibited by coincubation with gliotoxine (a nuclear factor-B inhibitor), dexamethasone, indomethacin (a cyclooxygenase inhibitor), GR-32191 (a TP prostanoid receptor antagonist), MK-476 (a cysteinyl leukotriene type 1 receptor antagonist), SR-140333 ϩ SR-48968 ϩ SR-142801 (neurokinin types 1, 2, and 3 tachykinin receptor antagonists) with or without HOE-140 (a bradykinin B 2 receptor antagonist), SB-203580 (an inhibitor of the 38-kDa mitogen-activated protein kinase, p38 MAPK ), or calphostin C (a protein kinase C blocker). Our results suggest that chronic exposure to fenoterol induces proinflammatory effects mediated by nuclear factor-B and pathways involving leukotrienes, prostanoids, bradykinin, tachykinins, protein kinase C, and p38 MAPK , leading to the regulation of smooth muscle contraction to ET-1 and ACh.␤ 2-agonists; airway sensitization; airway smooth muscle; endothelin-1; asthma THE FATAL ACUTE ASTHMA CASES attributable to fenoterol abuse in the 1980s in New Zealand started a controversy concerning the potential worsening of the bronchial hyperresponsiveness by the ␤ 2 -adrenoceptor agonists (7,14,42). Studies in animals and humans showed that chronic exposure to fenoterol or salbutamol induces a nonspecific bronchial sensitization, whereas the relaxant effects of these ␤ 2 -agonists on the airway smooth muscle are not decreased (11,59,60). The bronchial sensitization induced by fenoterol is similar to the sensitization provoked by ovalbumin in sensitized guinea pigs (60). Chronic administration of salbutamol at low doses to guinea pigs increases airway reactivity to histamine and methacholine (11). In humans, long-term use of salbutamol increases the bronchial hyperresponsiveness to histamine but does not cause subsensitization of ␤ 2 -adrenoceptors to salbutamol (59). In a bovine tracheal model, Katsunuma and colleagues (36) showed that prolonged incubation with fenoterol induced an increased contractile responsiveness to neurokinin A (NKA). In 1995, Peters and colleagues (47) suggested that the continuous activation of the intracellular signal transduction caused by the ␤ 2 -adrenoceptor stimulation could induce a proinflammatory process mediated by nuclear transcription factors in rat lung. A recent study in our institution showed that the transcription factor nuclear factor-B (NF-B) is involved in fenoterol-induced hyperresponsiveness to NKA in guinea pig isolated trachea (52).Endothelin-1 (ET-1) is a 21-amino acid peptide recently implicated in chronic inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (25,26,41,46). ET-1 is synthesized and metabolized in lung, and ET-1 receptors (ET A and ET B ) are widely distributed in airway cells (21,26...

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Proteomic identification of p38 MAP kinase substrates using in vitro phosphorylation

et al. 2013

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Protein phosphorylation is a major mechanism that regulates many basic cellular processes. Identification and characterization of substrates for a given protein kinase can lead to a better understanding of signal transduction pathways. However, it is still difficult to efficiently identify substrates for protein kinases. Here, we propose an integrated proteomic approach consisting of in vitro dephosphorylation and phosphorylation, phosphoprotein enrichment, and 2D-DIGE. Phosphatase treatment significantly reduced the complexity of the phosphoproteome, which enabled us to efficiently identify the substrates. We employed p38 mitogen-activated protein kinase (p38 MAP kinase) as a model kinase and identified 23 novel candidate substrates for this kinase. Seven selected candidates were phosphorylated by p38 MAP kinase in vitro and in p38 MAP kinase-activated cells. This proteomic approach can be applied to any protein kinase, allowing global identification of novel substrates.

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p38 Mitogen-activated protein kinase expression and activation in smooth muscle

Cited by 66 publications

References 26 publications

Activation of p38 Mitogen-Activated Protein Kinases by Endothelin and Noradrenaline in Small Arteries, Regulation by Calcium Influx and Tyrosine Kinases, and Their Role in Contraction

Activation of p38 Mitogen-Activated Protein Kinases by Endothelin and Noradrenaline in Small Arteries, Regulation by Calcium Influx and Tyrosine Kinases, and Their Role in Contraction

In vitro sensitization of human bronchus by β₂-adrenergic agonists

Proteomic identification of p38 MAP kinase substrates using in vitro phosphorylation

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p38 Mitogen-activated protein kinase expression and activation in smooth muscle

Cited by 66 publications

References 26 publications

Activation of p38 Mitogen-Activated Protein Kinases by Endothelin and Noradrenaline in Small Arteries, Regulation by Calcium Influx and Tyrosine Kinases, and Their Role in Contraction

Activation of p38 Mitogen-Activated Protein Kinases by Endothelin and Noradrenaline in Small Arteries, Regulation by Calcium Influx and Tyrosine Kinases, and Their Role in Contraction

In vitro sensitization of human bronchus by β2-adrenergic agonists

Proteomic identification of p38 MAP kinase substrates using in vitro phosphorylation

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In vitro sensitization of human bronchus by β₂-adrenergic agonists