Modulation of smooth muscle contractility by CHASM, a novel member of the smoothelin family of proteins

Borman, Meredith A.; MacDonald, Justin A.; Haystead, Timothy A.J.

doi:10.1016/j.febslet.2004.08.002

Cited by 36 publications

(65 citation statements)

References 44 publications

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“…The finding that SMTNL1 activity and intracellular localization are regulated by Ser-301 phosphorylation offers a mechanism to explain this paradox. In previous work we had shown that agonists that elevate intracellular cAMP or cGMP promote phosphorylation of Ser-301 in vivo, and phosphorylation of this amino acid inhibits the ability of SMTNL1 to inhibit PP1M in vitro (27,28). Herein we now show that phosphorylation Ser-301 also promotes translocation of SMTNL1 to the nucleus.…”

Section: Discussionsupporting

confidence: 55%

“…Ser-301 Phosphorylation Regulates Translocation of SMTNL1 to the Nucleus-SMNTL1 is phosphorylated at Ser-301 in vivo in response to agonists that elevate intracellular cGMP or cAMP (27,28). Our finding that SMTNL1 deletion induces expression of MYPT1 in both smooth and striated muscle tissues, and that this effect is greatly exaggerated during pregnancy, suggests a direct role for SMTNL1 in the regulation of MYPT1 expression.…”

Section: Pregnancy Regulates the Expression Of Mypt1 In Striated And mentioning

confidence: 76%

“…Gene deletion studies in mice demonstrated that SMTNL1 plays a role in cGMP/cAMP-mediated adaptations to exercise involving direct modulation of contractile activity in vascular smooth muscle. Inhibition of PP1M activity by SMTNL1 toward myosin and isolated light chains in vitro was also shown (27,28). Additionally, in striated muscle, SMTNL1 was found to be specifically expressed in Type 2a adaptive fibers and gene deletion promoted increased numbers of these fibers in males, suggesting a role in mediating both striated muscle as well as vascular plasticity in response to physiological stresses such as exercise (28).…”

mentioning

confidence: 90%

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Smoothelin-like 1 Protein Regulates Myosin Phosphatase-targeting Subunit 1 Expression during Sexual Development and Pregnancy*

Lontay

Bodoor

Weitzel

et al. 2010

Journal of Biological Chemistry

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Pregnancy coordinately alters the contractile properties of both vascular and uterine smooth muscles reducing systemic blood pressure and maintaining uterine relaxation. The precise molecular mechanisms underlying these pregnancy-induced adaptations have yet to be fully defined but are likely to involve changes in the expression of proteins regulating myosin phosphorylation. Here we show that smoothelin like protein 1 (SMTNL1) is a key factor governing sexual development and pregnancy induced adaptations in smooth and striated muscle. A primary target gene of SMTNL1 in these muscles is myosin phosphatase-targeting subunit 1 (MYPT1). Deletion of SMTNL1 increases expression of MYPT1 30 -40-fold in neonates and during development expression of both SMTNL1 and MYPT1 increases over 20-fold. Pregnancy also regulates SMTNL1 and MYPT1 expression, and deletion SMTNL1 greatly exaggerates expression of MYPT1 in vascular smooth muscle, producing a profound reduction in force development in response to phenylephrine as well as sensitizing the muscle to acetylcholine. We also show that MYPT1 is expressed in Type2a muscle fibers in mice and humans and its expression is regulated during pregnancy, suggesting unrecognized roles in mediating skeletal muscle plasticity in both species. Our findings define a new conserved pathway in which sexual development and pregnancy mediate smooth and striated muscle adaptations through SMTNL1 and MYPT1.

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Section: Discussionsupporting

confidence: 55%

Section: Pregnancy Regulates the Expression Of Mypt1 In Striated And mentioning

confidence: 76%

mentioning

confidence: 90%

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Smoothelin-like 1 Protein Regulates Myosin Phosphatase-targeting Subunit 1 Expression during Sexual Development and Pregnancy*

Lontay

Bodoor

Weitzel

et al. 2010

Journal of Biological Chemistry

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“…Both myosin light chain kinase and myosin phosphatase are regulated by several accessory proteins, and one such protein is smoothelin-like protein 1 (SMTNL1) (9). Mouse SMTNL1 is divided into two separate domains: a unique N-terminal domain (amino acids 1-346) and a C-terminal single, type-2 calponin homology domain (amino acids 346 -459) that is helix-rich and globular in structure essential for binding tropomysin (9,10). Physiological studies in smtnl1 Ϫ/Ϫ mice indicate that the protein plays a key role in modulating the contractile activity of smooth and striated muscle and is involved in adaptation in response to exercise and pregnancy (11,12).…”

Section: Smtnl1 Is a Bifunctional Co-regulator Of Pr-b Signaling And mentioning

confidence: 99%

“…Immunoprecipitation, Immunoblotting, and Mass Spectrometry-Uterus samples of WT and smtnl1 Ϫ/Ϫ mice in day 0 and 14 of pregnancy were homogenized as described previously (9). Samples were processed for immunoprecipitation (IP) and immunoblotting with specific antibodies against SMTNL1, PR, and ER␣.…”

Section: Mouse Colony Maintenance and Pregnancy Studies-the Smtnl1mentioning

confidence: 99%

Smoothelin-like 1 Protein Is a Bifunctional Regulator of the Progesterone Receptor during Pregnancy

Bodoor

Lontay

Safi

et al. 2011

Journal of Biological Chemistry

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During pregnancy, uterine smooth muscle (USM) coordinately adapts its contractile phenotype in order to accommodate the developing fetus and then prepare for delivery. Herein we show that SMTNL1 plays a major role in pregnancy to promote adaptive responses in USM and that this process is specifically mediated through interactions of SMTNL1 with the steroid hormone receptor PR-B. In vitro and in vivo SMTNL1 selectively binds PR and not other steroid hormone receptors. The physiological relationship between the two proteins was also established in global gene expression and transcriptional reporter studies in pregnant smtnl1 ؊/؊ mice and by RNA interference in progesterone-sensitive cell lines. We show that the contraction-associated and progestin-sensitive genes (oxytocin receptor, connexin 43, and cyclooxygenase-2) and prolactins are down-regulated in pregnant smtnl1 ؊/؊ mice. We suggest that SMTNL1 is a bifunctional co-regulator of PR-B signaling and thus provides a molecular mechanism whereby PR-B is targeted to alter gene expression patterns within USM cells to coordinately promote alterations in USM function during pregnancy.Uterine smooth muscle (USM) 5 cells show a high degree of plasticity and are capable of transforming their phenotype in response to a variety of physiological stresses, such as pregnancy. In pregnancy, USM cells go through a number of extensive phenotypic changes characterized by the expression of a distinct set of proteins (1, 2). In early pregnancy, USM cells proliferate rapidly under the influence of endocrine-stimulated growth factors (3). A significant increase in the expression of anti-apoptotic factors is a key feature of this proliferative phase (4). In midpregnancy, USM cells switch into a synthetic phase characterized by cellular hypertrophy, extracellular matrix remodeling, and activation of apoptotic pathways (3). The changes that occur during this phase are under the influence of both mechanical stimuli and endocrine hormones, such as progesterone (2). Toward parturition, the cells adopt a more contractile phenotype, characterized by an up-regulation in the expression of contraction-associated proteins (CAPs) (2). The phenotypic changes in this phase are modulated by mechanical stimuli and sex-related hormones, such as progesterone and estrogen. The molecular mechanisms regulating the transition of the USM through these different stages are limited, and investigation of these mechanisms is of great importance given the fact that preterm labor is still the leading cause of neonatal morbidity and mortality (5, 6).USM contraction is mainly regulated by phosphorylation of the regulatory light chain of myosin (MLC20) by Ca 2ϩ /calmodulin-dependent myosin light chain kinase, whereas relaxation is promoted by dephosphorylation of MLC20 by myosin phosphatase (7,8). Both myosin light chain kinase and myosin phosphatase are regulated by several accessory proteins, and one such protein is smoothelin-like protein 1 (SMTNL1) (9). Mouse SMTNL1 is divided into two separate domains: a uniqu...

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In situ Analysis of Smoothelin‐like 1 and Calmodulin Interactions in Smooth Muscle Cells by Proximity Ligation

Ulke‐Lemée¹,

Turner²,

MacDonald³

2015

J of Cellular Biochemistry

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The smoothelin-like 1 (SMTNL1) protein is the newest member of the smoothelin family of muscle proteins. Two calmodulin (CaM)-binding domains (CBD1 for Ca-CaM; CBD2 for apo-CaM) have been described for the SMTNL1 protein using in vitro assays. We now demonstrate in situ associations of SMTNL1 and CaM in A7r5 smooth muscle cells using the proximity ligation assay (PLA). We quantified CaM-SMTNL1 proximity events accurately after taking into account variations in protein expression levels. The refined method allows quantification of in situ proximity after transient transfection with an associated error of <10%. The proximity of SMTNL1 and CaM in A7r5 cells could be reduced by scrambling the amino acid sequence and mutation of large hydrophobic amino acids of CBD1. The truncation of CBD2 did not influence SMTNL1 proximity to CaM. Ultimately, we conclude that SMTNL1 forms complex interactions with CaM in smooth muscle cells, with a role for CBD1 and possibly the intrinsically disordered region.

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Modulation of smooth muscle contractility by CHASM, a novel member of the smoothelin family of proteins

Cited by 36 publications

References 44 publications

Smoothelin-like 1 Protein Regulates Myosin Phosphatase-targeting Subunit 1 Expression during Sexual Development and Pregnancy*

Smoothelin-like 1 Protein Regulates Myosin Phosphatase-targeting Subunit 1 Expression during Sexual Development and Pregnancy*

Smoothelin-like 1 Protein Is a Bifunctional Regulator of the Progesterone Receptor during Pregnancy

In situ Analysis of Smoothelin‐like 1 and Calmodulin Interactions in Smooth Muscle Cells by Proximity Ligation

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