Transforming growth factor-β signal transduction in epithelial cells

Yue, Jianbo; Mulder, Kathleen M.

doi:10.1016/s0163-7258(01)00143-7

Cited by 184 publications

(193 citation statements)

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“…The interplay between TGF-b and Ras pathway in activating the MAPK has been investigated and has been shown to vary dramatically depending on growth conditions and additional factors present in the milieu (Yue and Mulder, 2001). TGF-b is known to differentially modulate the oncogenic properties of Ras, either synergistically (Oft et al, 1996;Bost et al, 1999;Lehmann et al, 2000;Park et al, 2000;Santibanez et al, 2003) or antagonistically (Filmus et al, 1992;Kretzschmar et al, 1999;Saha et al, 2001;Santibanez et al, 2002;Kennedy et al, 2003;Vijayachandra et al, 2003;Wisdom et al, 2005), suggesting that the presence of additional factors and signaling crosstalk are key determinants of the eventual malignant outcome.…”

Section: Smad3 Deficiency Protects Mefs From Transformation Pr Arany mentioning

confidence: 99%

Smad3 deficiency inhibits v-ras-induced transformation by suppression of JNK MAPK signaling and increased farnesyl transferase inhibition

2007

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The ability of transforming growth factor-b (TGF-b) to modulate various effects on distinct cell lineages has been a central feature of its multi-faceted nature. The purpose of this study was to access the effects of deletion of a key TGF-b signal transducer, Smad3, on MAPK activation and v-Ras Ha -transformation of primary mouse embryonic fibroblasts (MEFs). We observe reduced TGF-b1 and v-ras Ha mediated activation of the JNK and ERK MAPK pathway upon ablation of Smad3. Further, Smad3-deficient MEFs demonstrate resistance to v-ras Ha -induced transformation while the absence of Smad3 results in increased inhibition of farnesyl transferase activity. Taken together, these observations demonstrate that the absence of Smad3 protects fibroblasts from oncogenic transformation by (i) augmenting farnesyl transferase inhibition and (ii) suppressing the Ras-JNK MAPK pathway. These results provide new insights into the molecular mechanisms involved in v-Ras Ha oncogene-induced mesenchymal phenotypic transformation.

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Section: Smad3 Deficiency Protects Mefs From Transformation Pr Arany mentioning

confidence: 99%

Smad3 deficiency inhibits v-ras-induced transformation by suppression of JNK MAPK signaling and increased farnesyl transferase inhibition

2007

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“…However, the cellular response to TGF␤ is greatly dependent on the type of cell involved. Although TGF␤ stimulates proliferation in fibroblasts and many other mesenchymal cells, it acts as a potent growth inhibitor in a variety of cell types, including epithelial, hematopoietic, and endothelial cells (Howe et al, 1991;Serini and Gabbiani, 1999;Bissell, 2001;Yue and Mulder, 2001). Three mammalian TGF␤ isoforms have been described to date, termed TGF␤-1, -2, and -3, which generally exhibit similar overall effects in vitro, yet they have distinct activities in vivo (Hartsough and Mulder, 1997;Kulkarni et al, 2002).…”

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confidence: 99%

A Unique Element in the Cytoplasmic Tail of the Type II Transforming Growth Factor-β Receptor Controls Basolateral Delivery

Murphy

Shapira

Henis

et al. 2007

MBoC

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Transforming growth factor (TGF)-␤ receptors stimulate diverse signaling processes that control a wide range of biological responses. In polarized epithelia, the TGF␤ type II receptor (T2R) is localized at the basolateral membranes. Sequential cytoplasmic truncations resulted in receptor missorting to apical surfaces, and they indicated an essential targeting element(s) near the receptor's C terminus. Point mutations in the full-length receptor confirmed this prediction, and a unique basolateral-targeting region was elucidated between residues 529 and 538 (LTAxxVAxxR) that was distinct, but colocalized within a clinically significant signaling domain essential for TGF␤-dependent activation of the Smad2/3 cascade. Transfer of a terminal 84 amino-acid fragment, containing the LTAxxVAxxR element, to the apically sorted influenza hemagglutinin (HA) protein was dominant and directed basolateral HA expression. Although delivery to the basolateral surfaces was direct and independent of any detectable transient apical localization, fluorescence recovery after photobleaching demonstrated similar mobility for the wild-type receptor and a missorted mutant lacking the targeting motif. This latter finding excludes the possibility that the domain acts as a cell membrane retention signal, and it supports the hypothesis that T2R sorting occurs from an intracellular compartment. INTRODUCTIONEpithelial cells form highly polarized monolayers that generate two morphologically and functionally distinct domains, an apical luminal facing domain and a basolateral domain that separates the epithelia from the underlying mesenchyme. Because the maintenance of cell polarity is dependent upon the asymmetrical distribution of proteins and lipids to precise locales on the cell surface (Rodriguez-Boulan et al., 2005), a number of cis-acting targeting signals have been described mediating protein sorting. For example, basolateral delivery is often regulated by minimal amino acid motifs in the cytoplasmic region of a wide range of membrane proteins, often being localized to juxtamembrane locales (Aroeti et al., 1998;Ikonen and Simons, 1998; RodriguezBoulan et al., 2005). Although extensive heterogeneity exists, certain features commonly arise in the amino acid sequences. Specifically, the targeting of many basolateral proteins, including the low-density lipoprotein receptor and vesicular stomatitis virus glycoprotein, have been demonstrated to be regulated by tyrosine-based motifs (Matter et al., 1992;Thomas et al., 1993) and a consensus sequence, YXX (where X is any amino acid and represents a large hydrophobic residue), has been proposed to be needed for correct trafficking (Hunziker and Mellman, 1991;Matter et al., 1992;Honing and Hunziker, 1995;Aroeti et al., 1998). Moreover, bipartite sorting signals and dihydrophobic residues such as dileucine (LL) motifs have also figured highly as effectors of basolateral trafficking (Hunziker and Fumey, 1994;Miranda et al., 2001). However, for many other reported basolaterally located proteins, the exac...

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“…Although Smad-dependent pathways are known to mediate TGF-β signaling, there is evidence that TGF-β may transmit signals through Smad-independent pathways [Akhurst and Derynck, 2001;Yue and Mulder, 2001;Moustakas et al, 2002;Miyazono et al, 2003;Shi and Massague, 2003]. In addition, TGF-β1 signaling pathways had been shown to crosstalk with other signaling pathways such as mitogen-acitvated protein kinase (MAPK) pathways and phosphatidylinositol-3 kinase (PI3-kinase) pathways [Cheng and Grande, 2002;Kim and Letterio, 2003].…”

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Nicotine inhibits myofibroblast differentiation in human gingival fibroblasts

Fang

Svoboda

2005

J of Cellular Biochemistry

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Cigarette smoking has been suggested as a risk factor for several periodontal diseases. It has also been found that smokers respond less favorably than non-smokers to periodontal therapy. Previous work in our lab has shown that nicotine inhibits human gingival cell migration. Since myofibroblasts play an important role in wound closure, we asked if nicotine affects gingival wound healing process by regulating myofibroblast differentiation. Human gingival fibroblasts (HGFs) from two patients were cultured in 10% fetal bovine serum cell culture medium. Cells were pretreated with different doses of nicotine (0, 0.01, 0.1, and 1 mM) for 2 h, and then incubated with transforming growth factor beta (TGF-β1) (0, 0.25, 0.5, and 1 ng/ml) with or without nicotine for 30 h. The expression level of α-smooth muscle actin (α-SMA), a specific marker for myofibroblasts, was analyzed by Western blots, immunocytochemistry, and real-time polymerase chain reaction (real-time PCR). Phosphorylated p38 mitogen-activated protein kinase (Phospho-p38 MAPK) activity was analyzed by Western blots. TGF-β1 induced an increase of α-SMA protein and mRNA expression, while nicotine (1 mM) inhibited the TGF-β1-induced expression of α-SMA but not β-actin. Nicotine treatment down-regulated TGF-β1-induced p38 MAPK phosphorylation. Our results demonstrated for the first time that nicotine inhibits myofibroblast differentiation in human gingival fibroblasts in vitro; supporting the hypothesis that delayed wound healing in smokers may be due to decreased wound contraction by myofibroblasts. Keywordshuman gingival fibroblasts; myofibroblasts; α smooth muscle actin; TGFβ; p38 MAP kinase Myofibroblasts are contractile cells that share characteristics of fibroblasts and smooth muscle cells [Tomasek et al., 2002]. One of the major features of myofibroblast differentiation is the expression of smooth muscle cell markers. These markers include α-SMA, γ-SMA, smooth muscle 22 (SM22), calponin, smoothelin, meta-vinculin, h-caldesmon [Halayko and Solway, 2001]. Among these, α-SMA has been suggested as the most reliable marker of myofibroblast differentiation [Gabbiani, 2003]. Also, Dr. Masur's lab demonstrated that myofibroblast differentiation was cell density dependent in corneal fibroblasts. They found that the lower the cell density when cells were seeded in culture, the more cells differentiated into myofibroblasts. However, the myofibroblast phenotype was not terminal. The cells lost the myofibroblast

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Transforming growth factor-β signal transduction in epithelial cells

Cited by 184 publications

References 357 publications

Smad3 deficiency inhibits v-ras-induced transformation by suppression of JNK MAPK signaling and increased farnesyl transferase inhibition

Smad3 deficiency inhibits v-ras-induced transformation by suppression of JNK MAPK signaling and increased farnesyl transferase inhibition

A Unique Element in the Cytoplasmic Tail of the Type II Transforming Growth Factor-β Receptor Controls Basolateral Delivery

Nicotine inhibits myofibroblast differentiation in human gingival fibroblasts

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