A Role for p38MAPK/HSP27 Pathway in Smooth Muscle Cell Migration

Hedges, Jason C.; Dechert, Melissa A.; Yamboliev, Ilia A.; Martin, J.L.; Hickey, Eileen; Weber, Lee A.; Gerthoffer, William T.

doi:10.1074/jbc.274.34.24211

Cited by 368 publications

(360 citation statements)

References 51 publications

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“…Indeed, treating ASMCs with CXCL1 significantly induced ERK-1/2 MAPK pathway activation, which mediated CXCL1 inhibition of ASMC migration. However, administering CXCL1 to ASMCs after siDARC resulted in a significant reduction in ERK-1/2 MAPK activity; concomitantly, we observed enhanced activity of p38 MAPK and downstream HSP27, a signaling pathway that has long been established as a modulator of cell migration (44). Interestingly, we found this enhancing effect to be mediated through CXCR2 in DARCdeficient ASMCs.…”

Section: Discussionsupporting

confidence: 53%

“…4C). Activation of HSP27 has been established as a regulator of cell migration downstream of the p38 MAPK pathway in both endothelial cells (43) and ASMCs (44). Therefore, we examined HSP27 in response to CXCL1 after siDARC and found that it also was activated at 5 min (siScram: 0.9-fold 6 0.35, siDARC: 1.79-fold 6 0.21; p , 0.05) and 15 min (siScram: 0.81-fold 6 0.25, siDARC: 1.73-fold 6 0.27; p , 0.05) after stimulation (Fig.…”

Section: Cxcl1 Is a Negative Regulator Of Asmc Migrationmentioning

confidence: 99%

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CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

Al-Alwan

Chang

Rousseau

et al. 2014

The Journal of Immunology

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Airway smooth muscle cell (ASMC) migration is an important mechanism postulated to play a role in airway remodeling in asthma. CXCL1 chemokine has been linked to tissue growth and metastasis. In this study, we present a detailed examination of the inhibitory effect of CXCL1 on human primary ASMC migration and the role of the decoy receptor, Duffy AgR for chemokines (DARC), in this inhibition. Western blots and pathway inhibitors showed that this phenomenon was mediated by activation of the ERK-1/2 MAPK pathway, but not p38 MAPK or PI3K, suggesting a biased selection in the signaling mechanism. Despite being known as a nonsignaling receptor, small interference RNA knockdown of DARC showed that ERK-1/2 MAPK activation was significantly dependent on DARC functionality, which, in turn, was dependent on the presence of heat shock protein 90 subunit α. Interestingly, DARC- or heat shock protein 90 subunit α–deficient ASMCs responded to CXCL1 stimulation by enhancing p38 MAPK activation and ASMC migration through the CXCR2 receptor. In conclusion, we demonstrated DARC’s ability to facilitate CXCL1 inhibition of ASMC migration through modulation of the ERK-1/2 MAPK–signaling pathway.

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Section: Discussionsupporting

confidence: 53%

Section: Cxcl1 Is a Negative Regulator Of Asmc Migrationmentioning

confidence: 99%

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

Al-Alwan

Chang

Rousseau

et al. 2014

The Journal of Immunology

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“…Here, we show that ALK5 mediates TGF-b1 signaling to enhance tumor cell motility and that all three MAP kinases (ERK, JNK, and p38 MAPK) contribute to this effect (Figure 1). The p38 MAPK pathway may enhance cell motility by regulating actin remodeling factor HSP27 (Hedges et al, 1999) and by affecting actin polymerization and cell contractility (Huot et al, 1998;Hedges et al, 1999;Bakin et al, 2002). MEK-ERK may regulate cell motility by preventing formation of extensive actin stress fibers via suppression of tropomyosin induction by TGF-b1 (Bakin et al, 2004) or inhibition of RhoA-Rho kinase pathway (Sahai et al, 2001;Pawlak and Helfman, 2002).…”

Section: Discussionmentioning

confidence: 99%

ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells

2006

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Transforming growth factor beta 1 (TGF-b1) is a potent tumor suppressor but, paradoxically, TGF-b1 enhances tumor growth and metastasis in the late stages of cancer progression. This study investigated the role of TGF-b type I receptor, ALK5, and three mitogen-activated protein kinases (MAPKs) in metastasis by breast cancer cell line MDA-MB-231. We show that autocrine TGF-b signaling in MDA-MB-231 cells is required for tumor cell invasion and tumor angiogenesis. Expression of kinaseinactive ALK5 reduces tumor invasion and formation of new blood vessels within the tumor orthotopic xenografts in severe combined immunodeficiency (SCID) mice. In contrast, constitutively active ALK5-T204D enhances tumor invasion and angiogenesis by stimulating expression of matrix metalloproteinase MMP-9/gelatinase-B. Ablation of MMP-9 in ALK5-T204D cells by RNA interference (RNAi) reduces tumor invasion and tumor growth. Importantly, RNAi-MMP-9 reduces tumor neovasculature and increases tumor cell death. Induction of MMP-9 by TGF-b-ALK5 signaling requires MEK-ERK but not JNK, p38 MAPK or Smad4. Dominant-negative MEK blocks and constitutively active MEK1 enhances MMP-9 expression. However, all three MAPK cascades (ERK, JNK and p38 MAPK) are required for TGF-b-mediated cell migration. Collectively, our results show that TGF-b-ALK5-MAPK signaling in tumor cells promotes tumor angiogenesis and MMP-9 is an important component of this program.

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“…They found that incubating the TSM strips in SB203580, a p38 MAP kinase inhibitor, resulted in an even greater degree of relengthening with the force oscillations. They speculated that p38 MAPK inhibition resulted in reduced phosphorylation of heat shock protein (HSP)27, a downstream protein that has been found to cap actin filaments when inactivated, uncapping when phosphorylated (23,24). They speculated that activated HSP27 allowed for increased actin filament polymerization, longer actin filaments in the airway smooth muscle cytoskeleton resulting in a stiffer muscle (23), and, concomitantly, less oscillation-induced relengthening (2-4, 21, 22).…”

Section: Mechanistic Explanations From In Vitro Studiesmentioning

confidence: 99%

Force Fluctuation induced Relengthening of Acetylcholine-contracted Airway Smooth Muscle

Mitchell¹,

Dowell²,

Solway³

et al. 2008

Proceedings of the American Thoracic Society

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Superimposition of force fluctuations on contracted tracheal smooth muscle (TSM) has been used to simulate normal breathing. Breathing has been shown to reverse lung resistance of individuals without asthma and animals given methacholine to contract their airways; computed tomography scans also demonstrated bronchial dilation after a deep inhalation in normal volunteers. This reversal of airway resistance and bronchial constriction are absent (or much diminished) in individuals with asthma. Many studies have demonstrated that superimposition of force oscillations on contracted airway smooth muscle results in substantial smooth muscle lengthening. Subsequent studies have shown that this force fluctuation-induced relengthening (FFIR) is a physiologically regulated phenomenon. We hypothesized that actin filament length in the smooth muscle of the airways regulates FFIR of contracted tissues. We based this hypothesis on the observations that bovine TSM strips contracted using acetylcholine (ACh) demonstrated amplitude-dependent FFIR that was sensitive to mitogen-activated protein kinase (p38 MAPK) inhibition-an upstream regulator of actin filament assembly. We demonstrated latrunculin B (sequesters actin monomers thus preventing their assimilation into filaments resulting in shorter filaments) greatly increases FFIR and jasplakinolide (an actin filament stabilizer) prevents the effects of latrunculin B incubation on strips of contracted canine TSM. We suspect that p38 MAPK inhibition and latrunculin B predispose to shorter actin filaments. These studies suggest that actin filament length may be a key determinant of airway smooth muscle relengthening and perhaps breathing-induced reversal of agonist-induced airway constriction. Keywords: actin filament length; latrunculin B; jasplakinolideMany studies have demonstrated that superimposition of force oscillations on contracted airway smooth muscle results in substantial smooth muscle lengthening in vitro (1-4), a phenomenon we refer to as force fluctuation-induced relengthening (FFIR). It has been proposed that imposition of these force oscillations simulate the effect of breathing on airway responsiveness and caliber. Shen and coworkers demonstrated in ventilated rabbits that breathing reduced methacholine-elicited airway resistance in a tidal volume-dependent manner (5). In normal individuals who demonstrated increased airway resistance to inhaled methacholine, the degree of bronchoconstriction could be reversed again by normal, tidal breathing (6, 7) or by taking a single deep inspiration (8-10). This airway dilation with deep inspiration also was demonstrated directly by looking at computed tomography (CT) scans of normal volunteers (8). Lung tethering forces on the conducting airways probably contributed to this dilation by loading the smooth muscle in the bronchiolar walls (8-10). However, this reversal of bronchoconstriction with breathing or deep inspiration is absent or minimal in individuals with asthma (9, 10); their airways remain constricted to methacholin...

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A Role for p38MAPK/HSP27 Pathway in Smooth Muscle Cell Migration

Cited by 368 publications

References 51 publications

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells

Force Fluctuation induced Relengthening of Acetylcholine-contracted Airway Smooth Muscle

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