Role of c-Abl tyrosine kinase in smooth muscle cell migration

Cleary, Rachel A.; Wang, Ruping; Waqar, Omar; Singer, Harold A.; Tang, Dale D.

doi:10.1152/ajpcell.00327.2013

Cited by 36 publications

(71 citation statements)

References 42 publications

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“…2013a,b, 2014a; Chen and Tang 2014; Cleary et al. 2014). In addition, c-Abl has been implicated in the pathogenesis of airway remodeling, a key feature of asthma (Rhee et al.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-203 negatively regulates c-Abl, ERK1/2 phosphorylation, and proliferation in smooth muscle cells

2015

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The nonreceptor tyrosine kinase c-Abl has a role in regulating smooth muscle cell proliferation, which contributes to the development of airway remodeling in chronic asthma. MicroRNAs (miRs) are small noncoding RNA molecules that regulate gene expression by binding to complementary sequences in the 3′ untranslated regions (3′ UTR) of target mRNAs. Previous analysis suggests that miR-203 is able to bind to the 3′ UTR of human c-Abl mRNA. In this report, treatment with miR-203 attenuated the expression of c-Abl mRNA and protein in human airway smooth muscle (HASM) cells. Furthermore, transfection with an miR-203 inhibitor enhanced the expression of c-Abl at mRNA and protein levels in HASM cells. Treatment with platelet-derived growth factor (PDGF) induced the proliferation and ERK1/2 phosphorylation in HASM cells. Exposure to miR-203 attenuated the PDGF-stimulated proliferation and ERK1/2 phosphorylation in HASM cells. The expression of c-Abl at protein and mRNA levels was higher in asthmatic HASM cells, whereas the level of miR-203 was reduced in asthmatic HASM cells as compared to control HASM cells. Taken together, our present results suggest that miR-203 is a negative regulator of c-Abl expression in smooth muscle cells. miR-203 regulates smooth muscle cell proliferation by controlling c-Abl expression, which in turn modulates the activation of ERK1/2.

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“…2013a,b, 2014a; Chen and Tang 2014; Cleary et al. 2014). In addition, c-Abl has been implicated in the pathogenesis of airway remodeling, a key feature of asthma (Rhee et al.…”

Section: Discussionmentioning

confidence: 99%

“…2011; Cleary et al. 2014). In smooth muscle, c-Abl is necessary for force development in response to contractile activation (Anfinogenova et al.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-203 negatively regulates c-Abl, ERK1/2 phosphorylation, and proliferation in smooth muscle cells

2015

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“…In addition to hyperplasia and hypertrophy, airway smooth muscle cell migration contributes to the development of airway remodeling. Smooth muscle thickening in the airways may stem from migration of proliferating cells in the muscle bundles or recruitment of circulating precursor cells to the smooth muscle layer [1–3]. …”

Section: Introductionmentioning

confidence: 99%

“…Third, actomyosin activity increases to induce retraction of the rear. Fourth, focal adhesions at the cell rear are disassembled to allow whole cell body to move forward [1, 3, 4]. There is a wealth of evidence to suggest that the actin cytoskeleton, the intermediate filament network, and microtubules are involved in the regulation of cell motility (Fig.…”

Section: Introductionmentioning

confidence: 99%

The roles and regulation of the actin cytoskeleton, intermediate filaments and microtubules in smooth muscle cell migration

2017

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Smooth muscle cell migration has been implicated in the development of respiratory and cardiovascular systems; and airway/vascular remodeling. Cell migration is a polarized cellular process involving a protrusive cell front and a retracting trailing rear. There are three cytoskeletal systems in mammalian cells: the actin cytoskeleton, the intermediate filament network, and microtubules; all of which regulate all or part of the migrated process. The dynamic actin cytoskeleton spatially and temporally regulates protrusion, adhesions, contraction, and retraction from the cell front to the rear. c-Abl tyrosine kinase plays a critical role in regulating actin dynamics and migration of airway smooth muscle cells and nonmuscle cells. Recent studies suggest that intermediate filaments undergo reorganization during migration, which coordinates focal adhesion dynamics, cell contraction, and nucleus rigidity. In particular, vimentin intermediate filaments undergo phosphorylation and reorientation in smooth muscle cells, which may regulate cell contraction and focal adhesion assembly/disassembly. Motile cells are characterized by a front-rear polarization of the microtubule framework, which regulates all essential processes leading to cell migration through its role in cell mechanics, intracellular trafficking, and signaling. This review recapitulates our current knowledge how the three cytoskeletal systems spatially and temporally modulate the migratory properties of cells. We also summarize the potential role of migration-associated biomolecules in lung and vascular diseases.

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“…(Lassila et al, 2004) In contrast, Abl has been found to be expressed by VSMCs and to be involved in cell proliferation, migration and contraction. (Cleary et al, 2014) The tyrosine kinase c-kit is highly expressed in de-differentiated VSMCs in the aortic wall (Hollenbeck et al, 2004) suggesting that attenuation of VSMC proliferation and migration after imatinib treatment could partially be mediated via Abl and c-kit as well as by PDGFR-β.…”

Section: Imatinib Treatment Attenuates Growth and Inflammation Of Angmentioning

confidence: 99%

Targeting vascular remodeling in abdominal aortic aneurysm : To identify novel treatment strategies and drug candidates

Vorkapić¹

2016

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Abdominal aortic aneurysm (AAA) is a degenerative weakening of the aortic wall, mainly affecting elderly men with a prevalence of 4.4-7.7 %. AAA is characterized by medial and adventitial inflammatory cell infiltration associated with vascular remodeling of the extracellular matrix proteins such as collagen and elastin and with phenotypic modulation and loss of vascular smooth muscle cells (VSMCs). Although much research has been performed, the precise cellular and molecular pathways behind these processes are still poorly understood. The overall aim of this thesis was to target signaling pathways that affect vascular remodeling of AAA to potentially identify novel strategies and drug candidates for future treatment of aneurysmal diseases. In order to develop our understanding of the pathophysiology of AAA, we used the angiotensin (Ang) II-induced AAA animal model and human biopsies taken at end-stage of disease to recapitulate key aspects of disease formation.Innate immune receptors such as toll-like receptors (TLRs) are known to regulate immunological processes leading to the formation and progression of vascular disease including AAA. In paper I, we aimed to investigate the role of TLR signaling under the control of the TRIF adaptor protein in the formation of AAA. Human, aneurysmal aortas displayed increased expression of TLR3 and TLR4 in surface of macrophages and T lymphocytes. AngII-induced aneurysm formation was attenuated in mice lacking the Trif gene (ApoE −/− Trif −/− ), and these knockout mice presented with a more intact medial layer together with a reduced inflammatory response by macrophages and T lymphocytes and reduced levels of pro-inflammatory cytokines, chemokines, and proteases. Our results suggest an involvement of TRIF in the pathophysiology of AAA.Current management of AAA fully depends on imaging and surgical techniques, and drugbased therapies are still mostly ineffective. In paper II, we aimed to investigate the potential protective role of the tyrosine kinase inhibitor imatinib on the molecular mechanism involved in AAA formation. In AngII-infused ApoE −/− mice, 10 mg/kg imatinib per day affected several key features important in aneurysmal formation, including preservation of the medial layer of the VSMCs, reduced infiltration of CD3ε-positive T lymphocytes, and reduced gene expression of mast cell chymase, resulting in decreased aortic diameter and vessel wall thickness. These results highlight the importance of the tyrosine kinase inhibitor imatinib as a VI potential drug in the treatment of pathological vascular inflammation and remodeling in conditions such as AAA.In paper III, we aimed to investigate the role of adiponectin in experimentally induced AAA formation in mice. In mice with elevated adiponectin levels, AAA development was inhibited, and this was associated with reduced inflammatory cell infiltration, reduced medial degeneration of VSMCs and of elastin in the aortic vessel wall together with an improved systemic cytokine profile and the attenuation of periaorti...

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Role of c-Abl tyrosine kinase in smooth muscle cell migration

Cited by 36 publications

References 42 publications

MicroRNA-203 negatively regulates c-Abl, ERK1/2 phosphorylation, and proliferation in smooth muscle cells

MicroRNA-203 negatively regulates c-Abl, ERK1/2 phosphorylation, and proliferation in smooth muscle cells

The roles and regulation of the actin cytoskeleton, intermediate filaments and microtubules in smooth muscle cell migration

Targeting vascular remodeling in abdominal aortic aneurysm : To identify novel treatment strategies and drug candidates

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