G protein coupled receptors can transduce signals through carboxy terminal and linker region phosphorylation of Smad transcription factors

Dayati, Parisa; Babaahmadi‐Rezaei, Hossein; Sharifat, Narges; Kamato, Danielle; Little, Peter J.

doi:10.1016/j.lfs.2018.03.004

Cited by 17 publications

(16 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TGF-β mediated proteoglycan synthesis [20,32] and GAG gene expression [19,21] are regulated by the phosphorylation of transcription factor Smad2 in the linker region. Multiple signalling pathways are involved in Smad2 linker region phosphorylation [3,8]. In this study we investigated the role of the phosphorylation of In VSMCs, TGF-β mediated Smad2 linker region phosphorylation of the serine residues occurs via the activation of Erk and p38 but not Jnk [19,20].…”

Section: Discussionmentioning

confidence: 98%

“…TGF-β signals via canonical carboxy terminal phosphorylation of R-Smads (Smad2 in vascular smooth muscle cells (VSMC)) and non-canonical linker region phosphorylation of R-Smads [3,4]. The role of TGF-β signalling in cell biology was greatly expanded when we showed that the paradigm of G Protein Coupled Receptor (GPCR) transactivation of protein tyrosine kinase receptors extended to the transactivation of serine/threonine kinase receptors and specifically the Type I TGF-β Receptor (TGFBR1) [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes

Kamato

Burch

Zhou

et al. 2019

Cellular Signalling

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes

Kamato

Burch

Zhou

et al. 2019

Cellular Signalling

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, it was also reported that Golgi protein 73 (GP73) promotes EMT and invasion by Smad2 activation in HCC cells [ 135 ]. Moreover, G protein-coupled receptors and their ligands can transmit signals through linker and the C-terminal phosphorylation of Smad2/3 [ 136 ]. Down-regulation of Smad7 expression has been shown to promote HCC metastatic potential by facilitating EMT [ 137 ].…”

Section: Emt In Liver Fibrosis and Hcc Progressionmentioning

confidence: 99%

Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis

Yoshida

Matsuzaki

Murata

et al. 2018

Cancers

View full text Add to dashboard Cite

Chronic viral hepatitis is a global public health problem, with approximately 570 million persons chronically infected. Hepatitis B and C viruses increase the risk of morbidity and mortality from liver cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic complications that develop. Hepatitis virus infection induces transforming growth factor (TGF)-β, which influences microenvironments within the infected liver. TGF-β promotes liver fibrosis by up-regulating extracellular matrix production by hepatic stellate cells. TGF-β is also up-regulated in patients with HCC, in whom it contributes importantly to bringing about a favorable microenvironment for tumor growth. Thus, TGF-β is thought to be a major factor regulating liver fibrosis and carcinogenesis. Since TGF-β carries out regulatory signaling by influencing the phosphorylation of Smads, we have generated several kinds of phospho-specific antibodies to Smad2/3. Using these, we have identified three types of phospohorylated forms: COOH-terminally phosphorylated Smad2/3 (pSmad2C and pSmad3C), linker phosphorylated Smad2/3 (pSmad2L and pSmad3L), and dually phosphorylated Smad3 (pSmad2L/C and pSmad3L/C). TGF-β-mediated pSmad2/3C signaling terminates cell proliferation; on the other hand, cytokine-induced pSmad3L signaling accelerates cell proliferation and promotes fibrogenesis. This review addresses TGF-β/Smad signal transduction in chronic liver injuries and carcinogenic processes. We also discuss the reversibility of Smad signaling after antiviral therapy.

show abstract

“…Besides these determinants, signal diversity may also result from modulatory interactions/crosstalk with other signaling pathways which are exerted at different levels of the signaling cascade. For instance, SMADs are phosphorylated in the linker region by kinases activated in response to tyrosine kinase receptors like the EGF receptor (EGFR) [ 14 , 15 , 16 ]. This non-canonical Smad signaling may block a particular SMAD-dependent response such as growth inhibition thereby enhancing the growth-promoting function of EGFR.…”

Section: Tgf-β Pars and Sphingosine-1-phosphate As A Mediator Bementioning

confidence: 99%

“…GPCRs can transduce signals not only through C-terminal but also through linker region phosphorylation of SMADs. Linker region phosphorylation arises due to activation of kinases including those downstream of the transactivation of the EGFR [ 14 , 15 , 16 ].…”

Section: Types Of Tgf-β–par2 and Tgf-β–par1 Interactionsmentioning

confidence: 99%

Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer

Ungefroren

Gieseler

Kaufmann

et al. 2018

IJMS

View full text Add to dashboard Cite

Both signaling by transforming growth factor-β (TGF-β) and agonists of the G Protein-coupled receptors proteinase-activated receptor-1 (PAR1) and -2 (PAR2) have been linked to tissue fibrosis and cancer. Intriguingly, TGF-β and PAR signaling either converge on the regulation of certain matrix genes overexpressed in these pathologies or display mutual regulation of their signaling components, which is mediated in part through sphingosine kinases and sphingosine-1-phosphate and indicative of an intimate signaling crosstalk between the two pathways. In the first part of this review, we summarize the various regulatory interactions that have been discovered so far according to the organ/tissue in which they were described. In the second part, we highlight the types of signaling crosstalk between TGF-β on the one hand and PAR2/PAR1 on the other hand. Both ligand–receptor systems interact at various levels and by several mechanisms including mutual regulation of ligand–ligand, ligand–receptor, and receptor–receptor at the transcriptional, post-transcriptional, and receptor transactivation levels. These mutual interactions between PAR2/PAR1 and TGF-β signaling components eventually result in feed-forward loops/vicious cycles of matrix deposition and malignant traits that exacerbate fibrosis and oncogenesis, respectively. Given the crucial role of PAR2 and PAR1 in controlling TGF-β receptor activation, signaling, TGF-β synthesis and bioactivation, combining PAR inhibitors with TGF-β blocking agents may turn out to be more efficient than targeting TGF-β alone in alleviating unwanted TGF-β-dependent responses but retaining the beneficial ones.

show abstract

G protein coupled receptors can transduce signals through carboxy terminal and linker region phosphorylation of Smad transcription factors

Cited by 17 publications

References 52 publications

Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes

Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes

Clinico-Pathological Importance of TGF-β/Phospho-Smad Signaling during Human Hepatic Fibrocarcinogenesis

Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer

Contact Info

Product

Resources

About