Caldesmon

Marston, Steven B.; Huber, P.

doi:10.1016/b978-012078160-7/50009-3

Cited by 34 publications

(24 citation statements)

References 103 publications

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“…Predicted translation products were determined by using the ExPASy translation tool. lation, CaD is phosphorylated whereby CaD dissociates from TM, which displaces on actin to expose myosin-binding sites for actomyosin interaction, leading to contraction (37). Previous studies have shown that VIP inhibits the dissociation of TM from CaD.…”

Section: Effect Of Hsp20 Phosphorylation On Ach-induced Association Omentioning

confidence: 99%

Phosphorylated HSP20 modulates the association of thin-filament binding proteins: caldesmon with tropomyosin in colonic smooth muscle

Somara

Gilmont

Varadarajan

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Somara S, Gilmont RR, Varadarajan S, Bitar KN. Phosphorylated HSP20 modulates the association of thin-filament binding proteins: caldesmon with tropomyosin in colonic smooth muscle. Am J Physiol Gastrointest Liver Physiol 299: G1164 -G1176, 2010. First published September 9, 2010 doi:10.1152/ajpgi.00479.2009.-Small heat shock proteins HSP27 and HSP20 have been implicated in regulation of contraction and relaxation in smooth muscle. Activation of PKC-␣ promotes contraction by phosphorylation of HSP27 whereas activation of PKA promotes relaxation by phosphorylation of HSP20 in colonic smooth muscle cells (CSMC). We propose that the balance between the phosphorylation states of HSP27 and HSP20 represents a molecular signaling switch for contraction and relaxation. This molecular signaling switch acts downstream on a molecular mechanical switch [tropomyosin (TM)] regulating thin-filament dynamics. We have examined the role of phosphorylation state(s) of HSP20 on HSP27-mediated thin-filament regulation in CSMC. CSMC were transfected with different HSP20 phosphomutants. These transfections had no effect on the integrity of actin cytoskeleton. Cells transfected with 16D-HSP20 (phosphomimic) exhibited inhibition of acetylcholine (ACh)-induced contraction whereas cells transfected with 16A-HSP20 (nonphosphorylatable) had no effect on ACh-induced contraction. CSMC transfected with 16D-HSP20 cDNA showed significant decreases in 1) phosphorylation of HSP27 (ser78); 2) phosphorylation of PKC-␣ (ser657); 3) phosphorylation of TM and CaD (ser789); 4) ACh-induced phosphorylation of myosin light chain; 5) ACh-induced association of TM with HSP27; and 6) ACh-induced dissociation of TM from caldesmon (CaD). We thus propose the crucial physiological relevance of molecular signaling switch (phosphorylation state of HSP27 and HSP20), which dictates 1) the phosphorylation states of TM and CaD and 2) their dissociations from each other.relaxation; heat shock protein; molecular signaling switch; molecular mechanical switch; smooth muscle contraction AGONIST-INDUCED INCREASES in intracellular Ca 2ϩ concentrations have been implicated in the initiation of smooth muscle contraction (42,46, 54,61). Although phosphorylation of regulatory myosin light chains (MLC 20 ) by activation of Ca 2ϩ / calmodulin-dependent myosin light chain kinase (MLCK) is the key mechanism for initiation of smooth muscle contraction, inactivation of myosin light chain phosphatase (MLCP) is the key mechanism for maintenance of smooth muscle contraction (25). However, maintenance of force upon decrease in intracellular calcium concomitant with decrease in phosphorylation of MLC 20 is associated with thin-filament regulation (18,36,38,64). Thin-filament regulation explains the maintenance of tone at low MLC 20 phosphorylation. Thin-filament regulation modulates the interaction of actin molecules of the thin filament with myosin heads of the thick filament for contraction to occur (10,20,53,65).Relaxation of smooth muscle occurs either as a result of removal of the con...

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Section: Effect Of Hsp20 Phosphorylation On Ach-induced Association Omentioning

confidence: 99%

Phosphorylated HSP20 modulates the association of thin-filament binding proteins: caldesmon with tropomyosin in colonic smooth muscle

Somara

Gilmont

Varadarajan

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…There are two CaD isoforms derived from a single gene (7): the heavy form (h-CaD) is specifically expressed in smooth muscle cells (8 -10), and the light form (l-CaD) is ubiquitously expressed (11,12). In smooth muscle cells the elongated h-CaD binds with its two end domains simultaneously to myosin and actin (13), and regulates the actomyosin interaction in a Ca 2ϩ /calmodulin (CaM)-and phosphorylation-dependent manner (14). Significantly, during smooth muscle relaxation h-CaD remains bound to the contractile apparatus, and the actin filaments are only moderately disassembled.…”

mentioning

confidence: 99%

Differential Effects of Caldesmon on the Intermediate Conformational States of Polymerizing Actin

Huang

Grabarek²,

Wang³

2010

Journal of Biological Chemistry

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The actin-binding protein caldesmon (CaD) reversibly inhibits smooth muscle contraction. In non-muscle cells, a shorter CaD isoform co-exists with microfilaments in the stress fibers at the quiescent state, but the phosphorylated CaD is found at the leading edge of migrating cells where dynamic actin filament remodeling occurs. We have studied the effect of a C-terminal fragment of CaD (H32K) on the kinetics of the in vitro actin polymerization by monitoring the fluorescence of pyrene-labeled actin. Addition of H32K or its phosphorylated form either attenuated or accelerated the pyrene emission enhancement, depending on whether it was added at the early or the late phase of actin polymerization. However, the CaD fragment had no effect on the yield of sedimentable actin, nor did it affect the actin ATPase activity. Our findings can be explained by a model in which nascent actin filaments undergo a maturation process that involves at least two intermediate conformational states. If present at early stages of actin polymerization, CaD stabilizes one of the intermediate states and blocks the subsequent filament maturation. Addition of CaD at a later phase accelerates F-actin formation. The fact that CaD is capable of inhibiting actin filament maturation provides a novel function for CaD and suggests an active role in the dynamic reorganization of the actin cytoskeleton.

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“…CaD is present in two isoforms (for reviews, see [1,13,14]: h-CaD (the smooth muscle or the high molecular weight form) and l-CaD (the nonmuscle or the low molecular weight form). In mammals both forms are derived from a single gene by alternative splicing [15].…”

mentioning

confidence: 99%

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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Caldesmon

Cited by 34 publications

References 103 publications

Phosphorylated HSP20 modulates the association of thin-filament binding proteins: caldesmon with tropomyosin in colonic smooth muscle

Phosphorylated HSP20 modulates the association of thin-filament binding proteins: caldesmon with tropomyosin in colonic smooth muscle

Differential Effects of Caldesmon on the Intermediate Conformational States of Polymerizing Actin

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

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