Smad and p38 MAP Kinase-mediated Signaling of Proteoglycan Synthesis in Vascular Smooth Muscle

Dadlani, Harsha M; Ballinger, Mandy L.; Osman, Narin; Getachew, Robel; Little, Peter J.

doi:10.1074/jbc.m703125200

Cited by 60 publications

(92 citation statements)

References 37 publications

(50 reference statements)

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“…Thus, notwithstanding the involvement of TGF-β1 in CAVD, blocking those pathways may not be an option for treating CAVD and atherosclerosis. However, recent evidence has shown that TGF-β1 signalling pathways are much more complex and can involve tyrosine and serine/threonine phosphorylation and activation of MAP kinases , particularly ERK and p38 [56][57][58]. This investigation demonstrated a small but not statistically significant level of MAP kinase activity in VICs associated with TGFβ1-mediated Smad phosphorylation however this may reflect the 4 hour time point studied.…”

Section: We Investigated the Signaling Pathways Through Which Tgf-β1 contrasting

confidence: 42%

“…In addition to Smad, Erk1/2 and p38 MAP kinases are involved in the regulation of GAG synthesis in vascular smooth muscle cells. [58,49]. Therefore, further investigations may provide an opportunity to discover Smad-independent TGF-β1 mediated signaling pathways that are associated with diseases processes and not immune functions, and that may well serve as more therapeutically useful targets for CAVD prevention and provides further strong impetus for studying the potential positive and/or negative effects of inhibiting these pathways in animal models of CAVD.…”

Section: We Investigated the Signaling Pathways Through Which Tgf-β1 mentioning

confidence: 99%

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Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

Osman

Grande-Allen

Ballinger

et al. 2013

Cardiovascular Pathology

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Section: We Investigated the Signaling Pathways Through Which Tgf-β1 contrasting

confidence: 42%

Section: We Investigated the Signaling Pathways Through Which Tgf-β1 mentioning

confidence: 99%

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

Osman

Grande-Allen

Ballinger

et al. 2013

Cardiovascular Pathology

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“…TGF-β is the most efficacious agonist of GAG hyperelongation in VSMCs mediating a very large increase in the size of biglycan molecules due to extensive elongation of the chondroitin sulphate GAG chains (Rostam et al 2016;Yang et al 2010;Osman et al 2011;Dadlani et al 2008;Burch et al 2010b). In addressing the directionality of transactivation signalling -GPCR to PTKR or PS/TKR or the reverse pathway, we examined the effect of TGF-β on cellular levels of IP 3 which would indicate reverse transactivation signalling and activation of PAR-1 and the generation of IP 3 as a downstream product following PAR-1 activation of PLCγ.…”

Section: Dual Gpcr Transactivation and The Effects On Vascular Smoothmentioning

confidence: 99%

Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

Chaplin

Thach

Hollenberg

et al. 2017

J. Cell Commun. Signal.

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G protein coupled receptor (GPCR) signalling is mediated by transactivation independent and transactivation dependent pathways. GPCRs transactivate protein tyrosine kinase receptors (PTKRs) and protein serine/threonine kinase receptors (PS/TKR). Since the initial observations of transactivation dependent signalling, there has been an effort to understand the mechanisms behind this phenomena. GPCR signalling has evolved to include biased signalling. Biased signalling, whereby selected ligands can activate the same GPCR that can generate multiple signals, but drive only a unique response. To date, there has been no focus on the ability of biased agonists to activate the PTKR and PS/TKR transactivation pathways differentially. As such, this represents a novel direction for future research. This review will discuss the main mechanisms of GPCR mediated receptor transactivation and the pathways involved in intracellular responses.

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“…The phorbol ester PMA also stimulates phosphorylation and activation of p38 MAP kinase in ASMCs (45). We have recently demonstrated that transforming growth factor ␤-1-mediated GAG chain elongation is mediated via the canonical Smad pathway but also invokes p38 MAP kinase signaling (46). PDGF-mediated p38 MAP kinase phosphorylation in ASMCs is not blocked by the upstream ERK inhibitor PD98095 as used in the present studies (44).…”

Section: Discussionmentioning

confidence: 65%

Platelet-derived Growth Factor Differentially Regulates the Expression and Post-translational Modification of Versican by Arterial Smooth Muscle Cells through Distinct Protein Kinase C and Extracellular Signal-regulated Kinase Pathways

Cardoso¹,

Little

Ballinger

et al. 2010

Journal of Biological Chemistry

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The synthesis of proteoglycans involves steps that regulate both protein and glycosaminoglycan (GAG) synthesis, but it is unclear whether these two pathways are regulated by the same or different signaling pathways. We therefore investigated signaling pathways involved in platelet-derived growth factor (PDGF)-mediated increases in versican core protein and GAG chain synthesis in arterial smooth muscle cells (ASMCs). PDGF treatment of ASMCs resulted in increased versican core protein synthesis and elongation of GAG chains attached to the versican core protein. The effects of PDGF on versican mRNA were blocked by inhibiting either protein kinase C (PKC) or the ERK pathways, whereas the GAG elongation effect of PDGF was blocked by PKC inhibition but not by ERK inhibition. Interestingly, blocking protein synthesis in the presence of cycloheximide abolished the PDGF effect, but not in the presence of xyloside, indicating that GAG synthesis that results from PKC activation is independent from de novo protein synthesis. PDGF also stimulated an increase in the chondroitin-6-sulfate to chondroitin-4-sulfate ratio of GAG chains on versican, and this effect was blocked by PKC inhibitors. These data show that PKC activation is sufficient to cause GAG chain elongation, but both PKC and ERK activation are required for versican mRNA core protein expression. These results indicate that different signaling pathways control different aspects of PDGF-stimulated versican biosynthesis by ASMCs. These data will be useful in designing strategies to interfere with the synthesis of this proteoglycan in various disease states.

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Smad and p38 MAP Kinase-mediated Signaling of Proteoglycan Synthesis in Vascular Smooth Muscle

Cited by 60 publications

References 37 publications

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

Platelet-derived Growth Factor Differentially Regulates the Expression and Post-translational Modification of Versican by Arterial Smooth Muscle Cells through Distinct Protein Kinase C and Extracellular Signal-regulated Kinase Pathways

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