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TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis.

Papageorgis P - J Oncol (2015)

Bottom Line: Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues.In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis.These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Health Sciences, Program in Biological Sciences, European University Cyprus, 6 Diogenes Street, Engomi, 1516 Nicosia, Cyprus.

ABSTRACT
Retaining the delicate balance in cell signaling activity is a prerequisite for the maintenance of physiological tissue homeostasis. Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues. Aberrant TGFβ signaling activity regulates tumor progression in a cancer cell-autonomous or non-cell-autonomous fashion and these effects may be tumor suppressing or tumor promoting depending on the cellular context. The fundamental role of this pathway in promoting cancer progression in multiple stages of the metastatic process, including epithelial-to-mesenchymal transition (EMT), is also becoming increasingly clear. In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis. These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.

No MeSH data available.


Related in: MedlinePlus

Smad-dependent and independent TGFβ pathways. Active TGFβ ligands initiate signaling by binding to TGFβRIs and TGFβRIIs. TGFβ receptors exhibit kinase activities that are necessary for transducing canonical TGFβ signaling by phosphorylating Smads2/3. Activated R-Smads can form a heterotrimeric complex with Smad4 which associates with other cofactors in the nucleus to regulate the expression of TGFβ target genes. Furthermore, downstream signaling can also be transduced via auxiliary pathways such as various brunches of the Mek/Erk, the Rho-like GTPases, and the PI3K/Akt and the p38/MAPK pathways to modulate biological responses including epithelial-to-mesenchymal transition, cell adhesion, migration, and survival.
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fig1: Smad-dependent and independent TGFβ pathways. Active TGFβ ligands initiate signaling by binding to TGFβRIs and TGFβRIIs. TGFβ receptors exhibit kinase activities that are necessary for transducing canonical TGFβ signaling by phosphorylating Smads2/3. Activated R-Smads can form a heterotrimeric complex with Smad4 which associates with other cofactors in the nucleus to regulate the expression of TGFβ target genes. Furthermore, downstream signaling can also be transduced via auxiliary pathways such as various brunches of the Mek/Erk, the Rho-like GTPases, and the PI3K/Akt and the p38/MAPK pathways to modulate biological responses including epithelial-to-mesenchymal transition, cell adhesion, migration, and survival.

Mentions: Mechanistically, all TGFβ isoforms initiate signaling in a similar manner. The active TGFβ1 ligand initially binds TGFβRII followed by recruitment of the ALK5 (TGFβRI) at the plasma membrane. With the heteromeric receptor-ligand complex formed, TGFβRII phosphorylates TGFβRI in a conserved Glycine-Serine (GS)-rich domain [47] leading to the dissociation of the inhibitory FKBP12 protein from TGFβRI [48]. This conformational switch allows activated TGFβRI to interact with R-Smads (Smad2/3) through their MH2 domain [49] resulting in their phosphorylation at the conserved SSXS C-terminal motif [31, 50]. SARA (Smad anchor for receptor activation) is a FYVE domain-containing protein which plays a central role in recruiting R-Smads to the activated TGFβRI to facilitate receptor-mediated phosphorylation. It preferentially associates with unphosphorylated Smad2 and is released upon Smad2 phosphorylation by TGFβRI [51]. This phosphorylation event triggers the formation of a heterotrimeric complex between phosphorylated R-Smads (Smad2/3) and co-Smad (Smad4), which can translocate into the nucleus to modulate gene expression (Figure 1) [3]. Smads act as transcription factors in cooperation with other coactivators, such as CBP/p300, P/CAF, SMIF, FoxO, Sp1, c-Jun/c-Fos, Sertad1, or corepressors, such as E2F4/5-p107, ATF3, TGIF, Ski, SnoN, FoxG1, EVI1, and CTBP [50, 52–68]. Furthermore, Smads can also indirectly regulate gene expression by controlling epigenetic processes, such as chromatin remodeling [69, 70] or by maintaining promoter DNA methylation, which is critical in silencing epithelial gene expression in cells that have undergone epithelial-to-mesenchymal transition (EMT) [71].


TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis.

Papageorgis P - J Oncol (2015)

Smad-dependent and independent TGFβ pathways. Active TGFβ ligands initiate signaling by binding to TGFβRIs and TGFβRIIs. TGFβ receptors exhibit kinase activities that are necessary for transducing canonical TGFβ signaling by phosphorylating Smads2/3. Activated R-Smads can form a heterotrimeric complex with Smad4 which associates with other cofactors in the nucleus to regulate the expression of TGFβ target genes. Furthermore, downstream signaling can also be transduced via auxiliary pathways such as various brunches of the Mek/Erk, the Rho-like GTPases, and the PI3K/Akt and the p38/MAPK pathways to modulate biological responses including epithelial-to-mesenchymal transition, cell adhesion, migration, and survival.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4389829&req=5

fig1: Smad-dependent and independent TGFβ pathways. Active TGFβ ligands initiate signaling by binding to TGFβRIs and TGFβRIIs. TGFβ receptors exhibit kinase activities that are necessary for transducing canonical TGFβ signaling by phosphorylating Smads2/3. Activated R-Smads can form a heterotrimeric complex with Smad4 which associates with other cofactors in the nucleus to regulate the expression of TGFβ target genes. Furthermore, downstream signaling can also be transduced via auxiliary pathways such as various brunches of the Mek/Erk, the Rho-like GTPases, and the PI3K/Akt and the p38/MAPK pathways to modulate biological responses including epithelial-to-mesenchymal transition, cell adhesion, migration, and survival.
Mentions: Mechanistically, all TGFβ isoforms initiate signaling in a similar manner. The active TGFβ1 ligand initially binds TGFβRII followed by recruitment of the ALK5 (TGFβRI) at the plasma membrane. With the heteromeric receptor-ligand complex formed, TGFβRII phosphorylates TGFβRI in a conserved Glycine-Serine (GS)-rich domain [47] leading to the dissociation of the inhibitory FKBP12 protein from TGFβRI [48]. This conformational switch allows activated TGFβRI to interact with R-Smads (Smad2/3) through their MH2 domain [49] resulting in their phosphorylation at the conserved SSXS C-terminal motif [31, 50]. SARA (Smad anchor for receptor activation) is a FYVE domain-containing protein which plays a central role in recruiting R-Smads to the activated TGFβRI to facilitate receptor-mediated phosphorylation. It preferentially associates with unphosphorylated Smad2 and is released upon Smad2 phosphorylation by TGFβRI [51]. This phosphorylation event triggers the formation of a heterotrimeric complex between phosphorylated R-Smads (Smad2/3) and co-Smad (Smad4), which can translocate into the nucleus to modulate gene expression (Figure 1) [3]. Smads act as transcription factors in cooperation with other coactivators, such as CBP/p300, P/CAF, SMIF, FoxO, Sp1, c-Jun/c-Fos, Sertad1, or corepressors, such as E2F4/5-p107, ATF3, TGIF, Ski, SnoN, FoxG1, EVI1, and CTBP [50, 52–68]. Furthermore, Smads can also indirectly regulate gene expression by controlling epigenetic processes, such as chromatin remodeling [69, 70] or by maintaining promoter DNA methylation, which is critical in silencing epithelial gene expression in cells that have undergone epithelial-to-mesenchymal transition (EMT) [71].

Bottom Line: Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues.In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis.These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Health Sciences, Program in Biological Sciences, European University Cyprus, 6 Diogenes Street, Engomi, 1516 Nicosia, Cyprus.

ABSTRACT
Retaining the delicate balance in cell signaling activity is a prerequisite for the maintenance of physiological tissue homeostasis. Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues. Aberrant TGFβ signaling activity regulates tumor progression in a cancer cell-autonomous or non-cell-autonomous fashion and these effects may be tumor suppressing or tumor promoting depending on the cellular context. The fundamental role of this pathway in promoting cancer progression in multiple stages of the metastatic process, including epithelial-to-mesenchymal transition (EMT), is also becoming increasingly clear. In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis. These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.

No MeSH data available.


Related in: MedlinePlus