Activation of p38 MAP-Kinase and Caldesmon Phosphorylation Are Essential for Urokinase-Induced Human Smooth Muscle Cell Migration

Goncharova, Elena A.; Vorotnikov, Alexander V.; Gracheva, Elena O.; Wang, C.-L. Albert; Panettieri, Reynold A.; Stepanova, Victoria; Tkachuk, Vsevolod A.

doi:10.1515/bc.2002.012

Cited by 60 publications

(50 citation statements)

References 53 publications

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“…Both the spatial and temporal distributions of phospho-CaD strongly suggest that non-muscle CaD phosphorylation plays an important role in facilitating the remodeling of cytoskeleton during cell division, rather than just regulating cytokinesis per se. This conclusion is supported by the observations that CaD phosphorylation is required during cell migration and cell adhesion [54]. Now the process can be understood as follows: Like h-CaD in smooth muscle cells, l-CaD in nonmuscle cells is unphosphorylated at the resting state, where it binds to actin filaments and stabilizes the filamentous structure by strengthening the linkage between neighboring actin subunits, and by preventing binding of severing proteins.…”

Section: +mentioning

confidence: 70%

“…It may also tether to myosin II and stabilize actin bundles in the stress fibers. Upon stimulation, l-CaD becomes phosphorylated in the C-terminal domain, depending on the kinase, either at Ser497 and Ser527 by Erk in spreading and migrating cells [53,54], or at additional sites by cdc2 in dividing cells [43], leading to partial or complete dissociation from actin, allowing actin filament severing and/or disassembly. Several recent reports raised the possibility that both MAPK and cdc2 kinase are simultaneously activated under a wide range of conditions [10,11,55].…”

Section: +mentioning

confidence: 99%

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Phosphorylation of caldesmon during smooth muscle contraction and cell migration or proliferation

2006

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SummaryThe actin-binding protein caldesmon (CaD) exists both in smooth muscle (the heavy isoform, h-CaD) and non-muscle cells (the light isoform, l-CaD). In smooth muscles h-CaD binds to myosin and actin simultaneously and modulates the actomyosin interaction. In non-muscle cells l-CaD binds to actin and stabilizes the actin stress fibers; it may also mediate the interaction between actin and non-muscle myosins. Both h-and l-CaD are phosphorylated in vivo upon stimulation. The major phosphorylation sites of h-CaD when activated by phorbol ester are the Erk-specific sites, modification of which is attenuated by the MEK inhibitor PD98059. The same sites in l-CaD are also phosphorylated when cells are stimulated to migrate, whereas in dividing cells l-CaD is phosphorylated more extensively, presumably by cdc2 kinase. Both Erk and cdc2 are members of the MAPK family. Thus it appears that CaD is a downstream effector of the Ras signaling pathways. Significantly, the phosphorylatable serine residues shared by both CaD isoforms are in the C-terminal region that also contains the actin-binding sites. Biochemical and structural studies indicated that phosphorylation of CaD at the Erk sites is accompanied by a conformational change that partially dissociates CaD from actin. Such a structural change in h-CaD exposes the myosin-binding sites on the actin surface and allows actomyosin interactions in smooth muscles. In the case of non-muscle cells, the change in l-CaD weakens the stability of the actin filament and facilitates its disassembly. Indeed, the level of l-CaD modification correlates very well in a reciprocal manner with the level of actin stress fibers. Since both cell migration and cell division require dynamic remodeling of actin cytoskeleton that leads to cell shape changes, phosphorylation of CaD may therefore serve as a plausible means to regulate these processes. Thus CaD not only links the smooth muscle contractility and non-muscle motility, but also provides a common mechanism for the regulation of cell migration and cell proliferation.Abbreviations: BPM -benzophenone maleimide; CaD -caldesmon; CaM -calmodulin; EM -electron microscopy; Erk -extracellular signal-regulated kinase; FRET -fluorescence resonance energy transfer; GFP -green fluorescent protein; h-CaD -smooth muscle caldesmon; IAEDANS -5-(iodoacetamidoethyl) aminonaphthalene-1-sulfonic acid; l-CaD -non-muscle caldesmon; MAPK -mitogen activated protein kinase; MLCK -myosin light chain kinase; MS -mass spectrometry; Pak -p21-activated protein kinase; PMA -phorbol 12-myristate 13-acetate; Raf -rat aorta fibroblast cells; Tm -tropomyosin Remodeling of actin cytoskeleton plays a central role in a variety of cellular processes that involve shape change and movement. Malfunction of these processes could lead to pathological consequences, but how actin-mediated motility is regulated is only beginning to be understood. With recent

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Section: +mentioning

confidence: 70%

Section: +mentioning

confidence: 99%

Phosphorylation of caldesmon during smooth muscle contraction and cell migration or proliferation

2006

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“…Migration is required for each of these alternative mechanisms for smooth muscle hyperplasia. Migration of ASM can be induced by plateletderived growth factor [116,117], enhanced by cys-leukotrienes [118] modulated by b 2 -adrenoceptor agonists and glucocorticoids [119], with the latter agents losing activity when cells are seeded onto a matrix containing monomeric type-1 collagen [120,121].…”

Section: Asm Growth Responsesmentioning

confidence: 99%

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

An¹,

Bai²,

Bates³

et al. 2007

European Respiratory Journal

341

298

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Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma.As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling.Anti-inflammatory therapy, however, does not ''cure'' asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

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“…Interestingly, the same residues of the major phosphorylation sites during mitosis 172 are also phosphorylated when cultured smooth muscle cells are stimulated to migrate. 173,174 Since both ERK and cdc2 kinase are simultaneously activated under a wide range of conditions, [175][176][177] CaD phosphorylation may thus provide a common mechanism to link cell proliferation and cell migration, both requiring cell shape changes.…”

Section: Phosphorylation As a Regulatory Mechanismmentioning

confidence: 99%

Caldesmon and the Regulation of Cytoskeletal Functions

Wang

2008

Advances in Experimental Medicine and Biology

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Caldesmon (CaD) is an extraordinary actin-binding protein, because in addition to actin, it also binds myosin, calmodulin and tropomyosin. As a component of the smooth muscle and nonmuscle contractile apparatus CaD inhibits the actomyosin ATPase activity and its inhibitory action is modulated by both Ca 2+ and phosphorylation. The multiplicity of binding partners and diverse biochemical properties suggest CaD is a potent and versatile regulatory protein both in contractility and cell motility. However, after decades of investigation in numerous laboratories, hard evidence is still lacking to unequivocally identify its in vivo functions, although indirect evidence is mounting to support an important role in connection with the actin cytoskeleton. This chapter reviews the highlights of the past findings and summarizes the current views on this protein, with emphasis of its interaction with tropomyosin.

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Activation of p38 MAP-Kinase and Caldesmon Phosphorylation Are Essential for Urokinase-Induced Human Smooth Muscle Cell Migration

Cited by 60 publications

References 53 publications

Phosphorylation of caldesmon during smooth muscle contraction and cell migration or proliferation

Phosphorylation of caldesmon during smooth muscle contraction and cell migration or proliferation

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

Caldesmon and the Regulation of Cytoskeletal Functions

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