NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

Cover of Madame Curie Bioscience Database

Madame Curie Bioscience Database [Internet].

Show details

TGFβ-dependent Epithelial-Mesenchymal Transition

and .

Summary

The transforming growth factor β (TGFβ) is involved in a whole range of bio logical functions, from cell growth to cell differentiation and apoptosis. The role of TGFβ in epithelial-mesenchymal-transitions (EMTs) has been shown for both embryonic development and tumorigenesis. All three TGFβ mammalian isoforms - TGFβ1, TGFβ2 and TGFβ3 — can regulate EMTs, with distinct outcomes depending on the tissue and on the state of cell differentiation. This diversity in the TGFβ response relies on a complex network of signals starting with different sets of TGFβ receptors and subsequently involving distinct TGFβ-dependent pathways. The purpose of this review is to recapitulate the current knowledge on the various signaling pathways - including the Smads, Ras, p38MAPK, RhoA and PI3K — which, upon activation by TGFβ can together give rise to TGFβ-induced EMT phenotypes.

Introduction

The transforming growth factor β (TGFβ) is implicated in a wide variety of biological functions ranging from growth control to cell differentiation, immune response and apoptosis.1,2,3,4,5,6,7,8,9 The transforming growth factor beta (TGFβ) polypeptide superfamily includes over 40 related members belonging to the TGFβ, activin, nodal and BMP (bone morphogenetic) families which are conserved throughout species, including vertebrates, insects and nematodes.

Three forms of TGFβ are known in mammals, the TGFβ1, TGFβ2 and TGFβ3 which are homodimeric proteins of 25kDa and are 65 to 80% identical to one another. Although these three isoforms demonstrate overlapping properties, they also display specific features. This is illustrated for instance by the distinct roles of the 3 TGFβs in embryonic cardiac differentiation (see below) and, more generally, by the specific phenotypes of the murine knock-outs such as the defective haematopoiesis in TGFβ1 knock-outs, the abnormal lung development and cleft palate observed in TGFβ3 null mice or in the reduced apoptosis of Tgfbeta2(-/-) Tgfbeta3(-/ -) double-deficient mice.10-14 Supporting the notion that TGFβs play distinct roles during development, the three isoforms TGFβ1, TGFβ2 and TGFβ3 are differentially expressed during embryogenesis.15 More generally, the TGFβs can demonstrate antithetic physiological effects which will depend upon both the cell type, its state of differentiation and the cellular microenvironment.

The present review focuses on the role the three mammalian TGFβs, TGFβ1, TGFβ2 and TGFβ3, in the epithelial-mesenchymal-transitions (EMTs) which occur in both embryonic development and cancer progression and on the signaling pathways which are involved in these regulations.

TGFβ Signaling

The effects of TGFβ are triggered by the activation of heteromeric complexes of TGFβ transmembrane type II (TβRII) and type I (TβRI) receptors which leads to the phosphorylation of downstream targets. Whereas TβRII binds TGFβ1 and TGFβ3 with high affinity, its affinity for TGFβ2 is much poorer. Therefore, TGFβ2 signaling also depends upon type III receptors (TβRIII) which enable its binding to TβRII and TβRI. Ligand binding to TβRII results in activation of TβRI and downstream signaling. At least two types of TβRI are capable of interacting with TβRII. The ALK5 (activin-like receptor kinase 5) is considered as the prototypical TGFβ receptor whereas ALK2 can interact with the type II receptor for either TGFβ, activin or BMP (bone morphogenetic protein). Because these various receptors can be differentially expressed in the different cells of a given tissue, one gets a first hint as to how cells within the same microenvironment can respond differently to local TGFβ concentrations.

Several signaling pathways have been identified downstream of the TGFβ receptors, among which the Smad pathway is the best characterized (fig. 1). The R-Smads (TGFβ-Responsive Smads), Smad2 and Smad3, are cytoplasmic proteins which are activated at the cell membrane by the TGFβ receptors. They associate with the coSmad Smad4 and translocate to the nucleus where they bind target genes and regulate transcription.16-18 Aside from the thoroughly characterized Smad signaling pathway, the transforming growth factor β (TGFβ) signaling can lead to the activation of ERK (extracellular signal-regulated kinase), JNK (Jun N-terminal kinase) and p38MAPK (p38 mitogen-activated protein kinase).4 Although some of this signaling involves the kinase TAK1 (TGFβ—activated kinase 1),19-21 the mechanisms of these signaling pathways as well as their connection to the TGFβ receptors remain to be more precisely defined. Alternatively, activation of PI3K/Akt (phosphatidylinositol-3 kinase) as well as of the Rho GTPases have also been reported22,23 (fig. 2).

Figure 1. The Smad Signaling Pathway.

Figure 1

The Smad Signaling Pathway. TGFβ binding to type II and type I receptors (TβRII and TβRI) leads to receptor oligomerization and activation. Recruitment of the R-Smads to the receptor complex involves the membrane bound protein SARA (more...)

Figure 2. The TGFβ-dependent Signaling Pathways.

Figure 2

The TGFβ-dependent Signaling Pathways. TGFβ can induce Smad-independent signaling pathways. These include the three MAP kinase pathways leading to the activation of ERK, JNK and p38MAPK. TGFβ has also been shown to activate the phosphatidylinositol (more...)

Role of TGFβ in Tumorigenesis and EMT

TGFβ plays an ambiguous role as it is both a tumor suppressor and a tumor promoter.8,24,25 TGFβ was named transforming growth factorβ for its capacity to induce, together with TGFα, a transformed phenotype in normal rat kidney fibroblasts.26 Although TGFβ was originally purified from human placenta and platelets,27,28 most cells secrete it. Secretion of TGFβ is increased in many tumor cells which respond to TGFβ by enhanced invasiveness. This process, which contributes to metastasis formation, is due to an increased mesenchymal-transdifferentiation in epithelial cells.29 TGFβ was first shown to induce epithelial-mesenchymal-transitions (EMTs) in immortalized mammary epithelial NMuMG cells.30 This differentiation from epithelial to fibroblastic phenotype was observed within 16 hours after addition of TGFβ1 and was accompanied by a decreased expression of the epithelial markers E-cadherin, ZO-1, and desmoplakin I and II, an increased expression of mesenchymal fibronectin markers and by a reorganization of actin stress fibers. In a different study, mice with TGFβ1 expression targeted to keratinocytes and exposed to carcinogenesis treatment showed an enhanced malignant progression.31 It took several years for what appears now as a fundamental TGFβ-dependent physiological effect to come to the front line. In the past few years, there has been a wealth of data which further emphasized the role of TGFβ in regulating the epithelial to mesenchymal transition (see reviews 7,9,24, see also chapter 1: hay and chapter 2: Morali et al). The main features of the epithelial-mesenchymal transition (EMT) induced by TGFβ are a switch from mainly cytokeratin to mainly vimentin intermediate filaments, the formation of actin stress fibers and an enhancement of cell migration. Markers of TGFβ-induced EMT also include elevated expression of N-cadherin and delocalization of E-cadherin from cell junctions.32 The TGFβ-dependent EMTs can be fully reversible as shown in the initial experiments on NMuMG epithelial cells where removal of TGFβ1 restored the epithelial phenotype within two days.30 The reversibility of the TGFβ-dependent EMT was also demonstrated, in the dedifferentiated mesenchymal mouse colon carcinoma cells (CT26), by the overexpression of a dominant-negative type II TβR which induced mesenchymal-to-epithelial transition and inhibited in vitro invasiveness.33 Metastasis formation in these cells was completely abolished. Besides, reexpression of the wild-type TβRII restored the invasiveness of human colon carcinoma cells (hnPCC) which otherwise harbor a nonfunctional receptor and are noninvasive in vitro.33

Role of the Three TGFβ Isoforms and of Their Receptors in the EMT Process

Outside from their role in tumor EMTs, the TGFβs are also involved in epithelial-mesenchymal transitions which occur during embryogenesis as, for instance, during palatal or cardiac development. 11,34-36 The three TGFβ isoforms, TGFβ1, TGFβ2 and TGFβ3, show different spatial and temporal expression patterns in the embryo and their different physiological roles are acutely demonstrated by their distinct functions during the embryonic heart EMT. Whereas TGFβ2 and TGFβ3 are necessary respectively for chick endothelial cell separation and transformation, both growth factors have an opposite effect on chick epicardial cells as they inhibit their FGF-dependent EMT.37,38 The complexity further increases with apparently distinct requirements for TGFβ family members depending on the species, the mouse differing from the chick by the fact that only TGFβ2 is expressed in the endocardial cushions and plays a functional role in the endocardial cushion EMT,39 see also Chapter 4.

The combinatorial diversity seen for TGFβ family members is also observed for their receptor subunits. Outside from the two well characterized TβRI and TβRII cell surface receptors, TGFβ signaling can also depend on TβRIII which is known to enhance TGFβ2 signaling by presenting the TGFβ ligand to the type II receptor. Work by Boyer and Runyan (see chapter 4) showed that, during the EMT which occurs in chick heart, an antibody-mediated block of TβRIII activity inhibited the TGFβ2-dependent endothelial cell-cell separation while, interestingly, antibody inhibition of TβRII had no effect40 suggesting distinct receptor requirements for TGFβ-induced EMT which still need to be fully established.

Both ALK2 and ALK5 TβRI receptors are expressed in the chick atrioventricular cushion. Antibody-mediated receptor inactivation showed that ALK2, but not ALK5, was necessary for the TGFβ1-induced EMT. On the other hand, only ALK5 was able to mediate the TGFβ1-dependent regulation of PAI-1 transcription,41 which shows that activation of different type I receptor subunits can lead to distinct biological outcomes. The ALK2/TSK-7L receptor was also shown to mediate TGFβ-dependent transdifferentiation in mouse NMuMG mammary epithelial tumor cells as the overexpression of a kinase-dead ALK2 receptor prevented them from acquiring a fibroblastoid morphology in response to TGFβ1.30 Interestingly though, the EMT markers E-cadherin, ZO-1 or fibronectin still responded to TGFβ regulation and the cells also exhibited TGFβ-dependent growth inhibiton.30 In the same cells, neither activin A nor bone morphogenetic protein-7 (BMP-7), which nonetheless utilize the same receptor subunit, were able to induce the morphological transformations, i.e., reorganization of the actin cytoskeleton or down regulation of E-cadherin and β-catenin,42 which suggests that activation of ALK2 is necessary but not sufficient to induce EMT in NMuMG epithelial cells. In addition, Piek et al showed that overexpression of an activated ALK5 receptor could induce transdifferentiation within 24 hours of infection, as shown by the remodeling of the actin cytoskeleton.42 These independent observations could appear difficult to reconcile. However, they also raise the interesting possibility of divergent TGFβ signaling emerging from distinct TGFβ subunits and which can target distinct sets of EMT markers and which altogether can generate a full mesenchymal phenotype.

Mechanisms and Signaling Pathways Involved in TGFβ-dependent EMTs

The molecular mechanisms of TGFβ-induced EMTs are complex and presumably tissue-dependent. The existence of intricate regulatory networks could explain why the inhibition of a given signaling pathway sometimes shows little effect on the TGFβ-dependent EMT while it is found central by other experimental approaches. Overall, several signaling pathways emerge as being repeatedly found in the TGFβ-induced EMT process. Outside from the Smads, these pathways include signaling leading to the activation of Ras, p38MAPK, Rho or PI3K. The involvement of the various pathways and the crosstalks taking place are discussed below.

Role of the Smads

There have been somehow conflicting results concerning the role of the Smads in the TGFβ-induced EMTs. This ambiguity might be the consequence of concentration threshold levels needed to be passed to achieve transdifferentiation. Involvement of the Smads in the EMT process was shown for example by experiments performed in the mouse mammary epithelial cells (NMuMG) where Smad2 and Smad3 were overexpressed together with a constitutively active TβRI.42 It was also suggested that in order to achieve invasive properties, the Smads require cooperation with other pathways such as that of Ras,43 see also chapter 17: Boyer. Using squamous mouse carcinomas initiated by activating mutations in the Hras1 gene, Balmain and collaborators showed that activation of Smad2 in a background of mutant H-Ras induced an EMT characterized by a transformation from a differentiated state to a motile invasive stage. Overexpression of the mutant H-Ras by itself induced neither the changes in cell shape nor the expression of the microfilaments characteristic of the EMT.44

On the other hand, the role of the Smads was questioned by experiments where the overexpression of anti-Smads, like Smad7 or a Smad3 dominant negative mutant, blocked cell cycle progression of NMuMG cells and, still, had no affect on EMT markers like the E- and N-cadherin relocalization or the actin cytoskeleton remodeling.32 This suggested that TGFβ-induced EMTs can be achieved independently of the Smads or, alternatively, that they require cellular levels of the Smads unable to achieve cell cycle regulation. In any case, the TGFβ-dependent signalings which regulate cell motility and proliferation appear to use distinct pathways.

Role of Smad-independent Signaling Pathways

p38 MAP Kinase

The p38MAPK is involved in the signaling of various TGFβ family members. However, the molecular mechanisms which enable p38MAPK activation are not fully determined. Arteaga and collaborators provided evidence that the MKK3/6-p38MAPK-ATF2 pathway is rapidly activated in response to TGFβ and that it is involved in TGFβ-mediated EMT of NMuMG mouse mammary epithelial cells.45 The kinase activities of both TβRI and TβRII receptors were necessary for p38MAPK activation and EMT to occur. Alternatively, overexpression of an activated ALK5 receptor also resulted in EMT which was concomitant with phosphorylation of MKK3/6 and p38MAPK.45 The role of p38 for TGFβ-induced EMT in NMuMG cells was further substantiated by experiments by Zhang and collaborators who, in addition, could establish a dichotomy in the TGFβ signalings leading on one hand to EMT and on the other hand to TGFβ-dependent cell growth control.46 These results, together with the findings of Bhowmick et al47 suggested that p38MAPK activity is required, though not sufficient, to induce TGFβ-mediated EMT.

Rho and PI3K

Signaling through RhoA or the PI3-kinase/Akt pathway has also been proposed for TGFβ-dependent EMTs,23,32 see also chapter 18: Nakagawa et al. TGFβ1 rapidly activates RhoA and p160Rock in NMuMG mammary epithelial cells.32 This activation correlated with two markers of the TGFβ-dependent EMT, i.e., delocalization of E-cadherin from cell junctions and expression of N-cadherin at cell margins. Neither of these were affected by altering either the Rac1 or JNKAPF pathways. Interestingly, NMuMG cell proliferation remained sensitive to TGFβ during this EMT transition.32 At least two components of the TGFβ-induced EMT are regulated by the RhoA pathway, which lead to actin cytoskeleton remodeling and disassembly of the adherens junctions. This was shown in NMuMG cells that overexpressed a kinase dead mutant of p160ROCK unable to interact with Rho, which still underwent E-cadherin delocalization from the adherens junctions in response to TGFβ but failed to acquire stress fibers and a prototypical fibroblastoid morphology.

The phosphatidylinositide 3-kinase (PI3K)/Akt pathway was shown to contribute to EMT-related tight junctions disruption. This response correlated with the delocalization of E-cadherin, ZO-1 and integrin β1 from the cell junctions while cells acquired a spindle morphology. 23 By administrating to MMTV-PyVmT transgenic mice a soluble Fc:TGFβ type II receptor fusion protein containing the extracellular domain of the TβRII, Arteaga and collaborators established a correlation between the observed reduction of tumor cell motility, intravasion and metastasis formation and the inhibition of Akt activity.48 Such a role for the Akt protein kinase in EMT processes was recently confirmed by the expression of a constitutively active Akt in carcinoma lines which led to characteristic EMT modifications like down-regulation of the epithelial markers desmoplakin, E-cadherin and β-catenin and up-regulation of the fibroblastic marker vimentin.49

Cross-talk Between Signaling Pathways

TGFβ-dependent EMTs are either inhibited or enhanced by various signaling pathways. Cytokines which induce these pathways can be produced in an autocrine manner. Alternatively, they can be secreted by stromal cells and constitute therefore active mediators of the dialogue which often takes place between cells undergoing EMT and cells from the stroma. Such is the case, for instance, for colon carcinoma whose TGFβ1-dependent EMT is accelerated by the tumor necrosis factor-α (TNF-α) produced by the surrounding activated macrophages. 50 Members of the TGFβ-superfamily themselves can also regulate the TGFβ-dependent EMT process. Their role as well as the particular case of Ras are discussed below.

Role of Members of the TGFβ Superfamily

Members of the bone morphogenetic protein (BMP) family can have either enhancing or inhibiting properties on the TGFβ-induced EMTs, as illustrated by the myocardial BMP2 which acts in synergy with TGFβ3 for the initiation of EMT whereas BMP7 counteracts the TGFβ1-induced EMT in renal tubular epithelial cells.51,52

The Case of Ras

The relationships between TGFβ and Ras are complex because of the intermingling between the two signaling pathways. TGFβ can on its own activate the Ras/MAPK pathway. In addition, the Ras/MAPK pathway can be activated by other cytokines, such as EGF, and regulate various steps of Smad signaling (see for a review 21). Several reports indicate a synergy between TGFβ and Ras/MAPK pathways in promoting EMT. EGF-dependent activation of Ras/MAPK was shown to stimulate TGFβ-induced EMT.53 In nontransformed mammary epithelial cells, expression of a mutant Ras was shown to have two effects on the TGFβ response: it prevented growth inhibition by TGFβ1 and, in addition, promoted EMT.33,43,54 Importantly, the Ras-transformed fibroblastoid cells could secrete TGF-beta themselves, leading to autocrine amplification of the phenomenon. In kidney MDCK epithelial cells, sustained activation of Raf induced cell invasiveness which depended on Raf-induced secretion of TGFβ.55

Conclusion and Perspectives

A number of studies suggest that distinct TGFβ signaling pathways regulate growth inhibition and epithelial-mesenchymal-transition. This raises the fascinating possibility that antagonists specific for the EMT pathway might be generated, that do not affect the control of cell proliferation. Under such circumstances, one could envision drugs for cancer therapy which would provide a block to metastasis spreading, while keeping the powerful capacity of TGFβ to control cell proliferation. This should emphasize the current efforts in developing TGFβ signaling inhibitors.25

Acknowledgements

We are grateful to J.C. Dantonel for critical reading of the manuscript.

References

1.
Moses HL, Serra R. Regulation of differentiation by TGF-beta. Curr Opin Genet Dev. 1996;6:581–6. [PubMed: 8939725]
2.
Capdevila J, Belmonte JC. Extracellular modulation of the Hedgehog, Wnt and TGF-beta signalling pathways during embryonic development. Curr Opin Genet Dev. 1999;9:427–33. [PubMed: 10449357]
3.
Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309. [PubMed: 11057902]
4.
Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29:117–29. [PubMed: 11586292]
5.
Hill CS. TGF-beta signalling pathways in early Xenopus development. Curr Opin Genet Dev. 2001;11:533–40. [PubMed: 11532395]
6.
Gorelik L, Flavell RA. Transforming growth factor-beta in T-cell biology. Nat Rev. Immunol2002;2:46–53. [PubMed: 11905837]
7.
Moustakas A, Pardali K, Gaal A. et al. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett. 2002;82:85–91. [PubMed: 12008039]
8.
Wakefield LM, Roberts AB. TGF-beta signaling: Positive and negative effects on tumorigenesis. Curr Opin Genet Dev. 2002;12:22–9. [PubMed: 11790550]
9.
Govinden R, Bhoola KD. Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther. 2003;98:257–65. [PubMed: 12725873]
10.
Dickson MC, Martin JS, Cousins FM. et al. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development. 1995;121:1845–54. [PubMed: 7600998]
11.
Kaartinen V, Voncken JW, Shuler C. et al. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet. 1995;11:415–21. [PubMed: 7493022]
12.
Sanford LP, Ormsby I, Gittenberger-de Groot AC. et al. TGFbeta2 knockout mice have multiple developmental defects that are nonoverlapping with other TGFbeta knockout phenotypes. Development. 1997;124:2659–70. [PMC free article: PMC3850286] [PubMed: 9217007]
13.
Taya Y, O_Kane S, Ferguson MW. Pathogenesis of cleft palate in TGF-beta3 knockout mice. Development. 1999;126:3869–79. [PubMed: 10433915]
14.
Dunker N, Krieglstein K. Reduced programmed cell death in the retina and defects in lens and cornea of Tgfbeta2(-/-) Tgfbeta3(-/-) double-deficient mice. Cell Tissue Res. 2003 [PubMed: 12838410]
15.
Schmid P, Cox D, Bilbe G. et al. Differential expression of TGF beta 1, beta 2 and beta 3 genes during mouse embryogenesis. Development. 1991;111:117–30. [PubMed: 2015789]
16.
Wrana JL. Regulation of Smad activity. Cell. 2000;100:189–92. [PubMed: 10660041]
17.
Moustakas A, Souchelnytskyi S, Heldin CH. Smad regulation in TGF-beta signal transduction. J Cell Sci. 2001;114:4359–69. [PubMed: 11792802]
18.
Shi Y, Massague J. Mechanisms of tgf-Beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700. [PubMed: 12809600]
19.
Yamaguchi K, Nagai S, Ninomiya-Tsuji J. et al. XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. Embo J. 1999;18:179–87. [PMC free article: PMC1171113] [PubMed: 9878061]
20.
Behrens J. Cross-regulation of the Wnt signalling pathway: A role of MAP kinases. J Cell Sci. 2000;113(Pt 6):911–9. [PubMed: 10683140]
21.
Massague J. How cells read TGF-beta signals. Nat Rev Mol Cell Biol. 2000;1:169–78. [PubMed: 11252892]
22.
Hanafusa H, Ninomiya-Tsuji J, Masuyama N. et al. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. J Biol Chem. 1999;274:27161–7. [PubMed: 10480932]
23.
Bakin AV, Tomlinson AK, Bhowmick NA. et al. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275:36803–10. [PubMed: 10969078]
24.
Akhurst RJ, Derynck R. TGF-beta signaling in cancer-a double-edged sword. Trends Cell Biol. 2001;11:S44–51. [PubMed: 11684442]
25.
Dumont N, Arteaga CL. Targeting the TGFbeta signaling network in human neoplasia. Cancer Cell. 2003;3:531–6. [PubMed: 12842082]
26.
De LarcoJE, Todaro GJ. Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci USA. 1978;75:4001–5. [PMC free article: PMC392918] [PubMed: 211512]
27.
Frolik CA, Dart LL, Meyers CA. et al. Purification and initial characterization of a type beta transforming growth factor from human placenta. Proc Natl Acad Sci USA. 1983;80:3676–80. [PMC free article: PMC394113] [PubMed: 6602340]
28.
Assoian RK, Komoriya A, Meyers CA. et al. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem. 1983;258:7155–60. [PubMed: 6602130]
29.
Dumont N, Arteaga CL. Transforming growth factor-beta and breast cancer: Tumor promoting effects of transforming growth factor-beta. Breast Cancer Res. 2000;2:125–32. [PMC free article: PMC139434] [PubMed: 11250702]
30.
Miettinen PJ, Ebner R, Lopez AR. et al. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: Involvement of type I receptors. J Cell Biol. 1994;127:2021–36. [PMC free article: PMC2120317] [PubMed: 7806579]
31.
Cui W, Fowlis DJ, Bryson S. et al. TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell. 1996;86:531–42. [PubMed: 8752208]
32.
Bhowmick NA, Ghiassi M, Bakin A. et al. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell. 2001;12:27–36. [PMC free article: PMC30565] [PubMed: 11160820]
33.
Oft M, Heider KH, Beug H. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol. 1998;8:1243–52. [PubMed: 9822576]
34.
Potts JD, Runyan RB. Epithelial-mesenchymal cell transformation in the embryonic heart can be mediated, in part, by transforming growth factor beta. Dev Biol. 1989;134:392–401. [PubMed: 2744239]
35.
Proetzel G, Pawlowski SA, Wiles MV. et al. Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet. 1995;11:409–14. [PMC free article: PMC3855390] [PubMed: 7493021]
36.
Brown CB, Boyer AS, Runyan RB. et al. Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. Science. 1999;283:2080–2. [PubMed: 10092230]
37.
Boyer AS, Ayerinskas II, Vincent EB. et al. TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev Biol. 1999;208:530–45. [PubMed: 10191064]
38.
Morabito CJ, Dettman RW, Kattan J, Collier JM, Bristow J. Positive and negative regulation of epicardial-mesenchymal transformation during avian heart development. Dev Biol. 2001;234:204–15. [PubMed: 11356030]
39.
Camenisch TD, Molin DG, Person A. et al. Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev Biol. 2002;248:170–81. [PubMed: 12142029]
40.
Boyer AS, Runyan RB. TGFbeta Type III and TGFbeta Type II receptors have distinct activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev Dyn. 2001;221:454–9. [PubMed: 11500982]
41.
Lai YT, Beason KB, Brames GP. et al. Activin receptor-like kinase 2 can mediate atrioventricular cushion transformation. Dev Biol. 2000;222:1–11. [PubMed: 10885742]
42.
Piek E, Moustakas A, Kurisaki A. et al. TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci. 1999;112(Pt 24):4557–68. [PubMed: 10574705]
43.
Oft M, Peli J, Rudaz C. et al. TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev. 1996;10:2462–77. [PubMed: 8843198]
44.
Oft M, Akhurst RJ, Balmain A. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol. 2002;4:487–94. [PubMed: 12105419]
45.
Bakin AV, Rinehart C, Tomlinson AK. et al. p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci. 2002;115:3193–206. [PubMed: 12118074]
46.
Yu L, Hebert MC, Zhang YE. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. Embo J. 2002;21:3749–59. [PMC free article: PMC126112] [PubMed: 12110587]
47.
Bhowmick NA, Zent R, Ghiassi M. et al. Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity. J Biol Chem. 2001;276:46707–13. [PubMed: 11590169]
48.
Muraoka RS, Dumont N, Ritter CA. et al. Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest. 2002;109:1551–9. [PMC free article: PMC151012] [PubMed: 12070302]
49.
Grille SJ, Bellacosa A, Upson J. et al. The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 2003;63:2172–8. [PubMed: 12727836]
50.
Bates RC, Mercurio AM. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell. 2003;14:1790–800. [PMC free article: PMC165077] [PubMed: 12802055]
51.
Nakajima Y, Yamagishi T, Hokari S. et al. Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: Roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP) Anat Rec. 2000;258:119–27. [PubMed: 10645959]
52.
Zeisberg M, Hanai J, Sugimoto H. et al. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med. 2003;9:964–8. [PubMed: 12808448]
53.
Grande M, Franzen A, Karlsson JO. et al. Transforming growth factor-beta and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes. J Cell Sci. 2002;115:4227–36. [PubMed: 12376555]
54.
Janda E, Lehmann K, Killisch I. et al. Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: Dissection of Ras signaling pathways. J Cell Biol. 2002;156:299–313. [PMC free article: PMC2199233] [PubMed: 11790801]
55.
Lehmann K, Janda E, Pierreux CE. et al. Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: A mechanism leading to increased malignancy in epithelial cells. Genes Dev. 2000;14:2610–22. [PMC free article: PMC316988] [PubMed: 11040215]
Copyright © 2000-2013, Landes Bioscience.
Bookshelf ID: NBK6525

Views

  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...