Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells

Kamato, Danielle; Rostam, Muhamad Ashraf; Piva, Terrence J.; Babaahmadi‐Rezaei, Hossein; Getachew, Robel; Thach, Lyna; Bernard, Rebekah; Zheng, Wenhua; Little, Peter J.; Osman, Narin

doi:10.1111/jphp.12298

Cited by 27 publications

(26 citation statements)

References 41 publications

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“…In vascular endothelial cells, Smad2 linker region residues are phosphorylated by different serine/threonine kinases that alter plasminogen-activator inhibitor 1 mRNA expression (Kamato et al, 2014). Here we used two antibodies, with one detecting the cluster of serine residues (Ser245/250/255) and the second, the phosphorylated threonine residue (Thr220).…”

Section: Discussionmentioning

confidence: 99%

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Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Rostam

Shajimoon

Kamato

et al. 2018

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 99%

“…Site-specific antibody for phospho-Thr220 was used to investigate the involvement of the Thr220 residue (Matsuzaki et al, 2009;Kamato et al, 2014). We have previously reported that TGF-β treatment stimulates the phosphorylation of Thr220 with a peak response at 1 h (Rostam et al, 2016).…”

Section: Flavopiridol Effects On Tgf-β-stimulated Biglycan Synthesis mentioning

confidence: 99%

Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Rostam

Shajimoon

Kamato

et al. 2018

J Pharmacol Exp Ther

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“…[S/T]-P phosphorylation of SMADs by multiple kinases, including the JNKs (326,327), switches their interactions with YAP/TAZ transcription factor proteins toward binding to the NEDD4-like E3 ubiquitin ligase Smurf1 (328). In this example, one of the multiple WW domains of Smurf1 mediating this interaction requires the canonical PPxY motif, but the other recognizes phosphorylated motifs instead and it binds in a reverse orientation, thus promoting interaction and the subsequent degradation of SMAD1 (328).…”

Section: Jnk Phospho-switches Potentiating New Protein-protein Bindinmentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

386

350

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SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

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“…Reports by Chung et al (Chung et al 2013) demonstrate PAR-2 transactivation of TGFBR1 in their renal fibrosis model to have identical mechanisms to that occurring in our VSMCs model ) with the exception that MMPs are involved in the phosphorylation of Smad. The phosphorylation of Smad in the carboxy terminal is a direct result of the kinase activity of TGFBR1 directed to Smad2 or Smad3 (Kamato et al 2013(Kamato et al , 2014, however Smad transcription factors are also phosphorylated in the linkage region this response is not direct but is mediated via serine/threonine kinases (Kamato et al 2013). To expand on the role of MMPs in GPCRs mediated transactivation dependent signalling we used antibodies to both the phosphorylated Smad2 carboxy terminals and linker region (Kamato et al 2016a).…”

Section: Gpcr Transactivation Of Protein Serine/threonine Receptorsmentioning

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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Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells

Cited by 27 publications

References 41 publications

Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

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

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