Transforming growth factor-β signalling: Role and consequences of Smad linker region phosphorylation

Kamato, Danielle; Burch, Micah L; Piva, Terrence J.; Babaahmadi‐Rezaei, Hossein; Rostam, Muhamad Ashraf; Xu, Suowen; Zheng, Wenhua; Little, Peter J.; Osman, Narin

doi:10.1016/j.cellsig.2013.06.001

Cited by 212 publications

(183 citation statements)

References 89 publications

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“…Among the downstream signalling pathways involving in TGF‐β‐dependent renal interstitial fibrosis, Smads pathway is considered as the most critical one 31. TGF‐β1 signal is transduced through its cell membrane receptors I and II (TGFβ‐RI and TGFβ‐RII).…”

Section: Discussionmentioning

confidence: 99%

Acetyl‐11‐keto‐β‐boswellic acid ameliorates renal interstitial fibrosis via Klotho/TGF‐β/Smad signalling pathway

Liu

Shang

et al. 2018

J Cellular Molecular Medi

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Acetyl‐11‐keto‐β‐boswellic acid (AKBA), an active triterpenoid compound from the extract of Boswellia serrate, has been reported previously in our group to alleviate fibrosis in vascular remodelling. This study aimed to elucidate the in vivo and in vitro efficacy and mechanism of AKBA in renal interstitial fibrosis. The experimental renal fibrosis was produced in C57BL/6 mice via unilateral ureteral obstruction (UUO). Hypoxia‐induced HK‐2 cells were used to imitate the pathological process of renal fibrosis in vitro. Results showed that the treatment of AKBA significantly alleviated UUO‐induced impairment of renal function and improved the renal fibrosis by decreasing the expression of TGF‐β1, α‐SMA, collagen I and collagen IV in UUO kidneys. In hypoxia‐induced HK‐2 cells, AKBA displayed remarkable cell protective effects and anti‐fibrotic properties by increasing the cell viability, decreasing the lactate dehydrogenase (LDH) release and inhibiting fibrotic factor expression. Moreover, in obstructed kidneys and HK‐2 cells, AKBA markedly down‐regulated the expression of TGFβ‐RI, TGFβ‐RII, phosphorylated‐Smad2/3 (p‐Smad2/3) and Smad4 in a dose‐dependent fashion while up‐regulated the expression of Klotho and Smad7 in the same manner. In addition, the effects of AKBA on the Klotho/TGF‐β/Smad signalling were reversed by transfecting with siRNA‐Klotho in HK‐2 cells. In conclusion, our findings provide evidence that AKBA can effectively protect kidney against interstitial fibrosis, and this renoprotective effect involves the Klotho/TGF‐β/Smad signalling pathway. Therefore, AKBA could be considered as a promising candidate drug for renal interstitial fibrosis.

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Section: Discussionmentioning

confidence: 99%

Acetyl‐11‐keto‐β‐boswellic acid ameliorates renal interstitial fibrosis via Klotho/TGF‐β/Smad signalling pathway

Liu

Shang

et al. 2018

J Cellular Molecular Medi

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“…In endometrioma and deep endometriosis lesions, chronic inflammation and fibrosis represents a common finding and TGF-b signaling is critically involved in the fibrotic reaction (29,30), enhancing the expression of a fibrosis marker (31). TGF-b family members and AMH act through serine/threonine kinase receptors and Smad effectors, and the regulate Smad expression and phosphorylation in endometrial epithelial and stromal cells (13,14,32,33). In particular, AMH gains access to the Smad system through its specific type II receptor, sharing some biologic action with other TFG-b family members (34).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of antimüllerian hormone and its receptor in endometriosis

Carrarelli

Rocha

Belmonte

et al. 2014

Fertility and Sterility

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Objective: To evaluate antim€ ullerian hormone (AMH) and AMH receptor II (AMHRII) mRNA and protein expression in endometrium and in ovarian or deep lesions of women with endometriosis. Design: Prospective study. Setting: University hospitals in Italy and Brazil. Patients: Patients with endometriosis (n ¼ 55) and healthy women (n ¼ 45). Interventions: Specimens of endometrium obtained by hysteroscopy from patients with endometriosis and from healthy control subjects; specimens of ovarian endometriosis (n ¼ 29) or of deep endometriosis (n ¼ 26) were collected by laparoscopy. Serum samples were collected in some endometriotic patients (n ¼ 23) and healthy control subjects (n ¼ 20). Main Outcome Measure(s): AMH and AMHRII mRNA levels were evaluated by quantitative reverse-transcription polymerase chain reaction and protein localization by immunohistochemistry. AMH levels in tissue homogenates and in serum were assessed by ELISA. Result(s): Endometrium from women with endometriosis showed higher AMH and AMHRII mRNA levels than control women, with no significant differences between proliferative and secretory phases. Specimens collected from ovarian or deep endometriosis showed the highest AMH and AMHRII mRNA expression. Immunolocalization study confirmed the high AMH and AMHRII protein expression in endometriotic lesions. No difference of serum AMH levels between the groups was found. Conclusion(s):The increased AMH and AMHRII mRNA and protein expression in endometrium and in endometriotic lesions suggests a possible involvement of AMH in endometriosis.

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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 signalling: Role and consequences of Smad linker region phosphorylation

Cited by 212 publications

References 89 publications

Acetyl‐11‐keto‐β‐boswellic acid ameliorates renal interstitial fibrosis via Klotho/TGF‐β/Smad signalling pathway

Acetyl‐11‐keto‐β‐boswellic acid ameliorates renal interstitial fibrosis via Klotho/TGF‐β/Smad signalling pathway

Increased expression of antimüllerian hormone and its receptor in endometriosis

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

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