Phosphatidylinositol 3-Kinase Function Is Required for Transforming Growth Factor β-mediated Epithelial to Mesenchymal Transition and Cell Migration*

By Andrei V Bakin, A. Tomlinson, N. Bhowmick, H. Moses, Carlos L. Arteaga. Journal of Biological Chemistry, 2000

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We have studied the role of phosphatidylinositol 3-OH kinase (PI3K)-Akt signaling in transforming growth factor β (TGFβ)-mediated epithelial to mesenchymal transition (EMT). In NMuMG mammary epithelial cells, exogenous TGFβ1 induced phosphorylation of Akt at Ser-473 and Akt in vitro kinase activity against GSK-3β within 30 min. These responses were temporally correlated with delocalization of E-cadherin, ZO-1, and integrin β1 from cell junctions and the acquisition of spindle cell morphology. LY294002, an inhibitor of the p110 catalytic subunit of PI3K, and a dominant-negative mutant of Akt blocked the delocalization of ZO-1 induced by TGFβ1, whereas transfection of constitutively active p110 induced loss of ZO-1 from tight junctions. In addition, LY294002 blocked TGFβ-mediated C-terminal phosphorylation of Smad2. Consistent with these data, TGFβ-induced p3TP-Lux and p(CAGA)12-Lux reporter activities were inhibited by LY294002 and transiently expressed dominant-negative p85 and Akt mutants in NMuMG and 4T1 cells. Dominant-negative RhoA inhibited TGFβ-induced phosphorylation of Akt at Ser-473, whereas constitutively active RhoA increased the basal phosphorylation of Akt, suggesting that RhoA in involved in TGFβ-induced EMT. Finally, LY294002 and neutralizing TGFβ1 antibodies inhibited ligand-independent constitutively active Akt as well as basal and TGFβ-stimulated migration in 4T1 and EMT6 breast tumor cells. Taken together, these data suggest that PI3K-Akt signaling is required for TGFβ-induced transcriptional responses, EMT, and cell migration.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f333dd6f723f084ef9654d4dea03d6f3af412b93

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Citations in the corpus

EMT, the cytoskeleton, and cancer cell invasion (2009, background): “Among the candidates which are engaged by TGFβ-induced EMT are the small GTPases RhoA and Rac1 [12, 13], Ras [14], phosphoinositol–3 kinase (PI3K) [15], Mitogen-activated protein kinase (MAPK) [13], integrin-linked kinase (ILK) [16], and the Jagged1/Notch signaling pathway [17].”
Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis (2002, background): “…termed EMT) observed by others in different cell systems in response to Ras alone (Chen et al., 2000), Ras or Raf plus TGF (Oft et al., 1998; Lehmann et al., 2000), FGF, EGF, and SF/HGF (Thiery and Chopin, 1999; Boyer et al., 2000), and finally TGF alone (Piek et al., 1999; Bakin et al., 2000).”
TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. (2005, background): “Despite this, other evidence has supported the role of alternative signaling pathways in the same phenotypic response (Bakin et al., 2000; Bhowmick et al., 2001a; Bhowmick et al., 2001b; Bakin et al., 2002; Yu et al., 2002).”
Smad-dependent and Smad-independent pathways in TGF-β family signalling (2003, background): “TGF-β can also activate phosphatidylinositol-3-kinase (PI3K), as indicated by phosphorylation of its effector Ak”
TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis (2019, neutral): “TGF-β receptors interact with the regulatory p85 subunit of PI3K, resulting in activation of the PI3K/AKT pathway, which controls translational responses through mammalian target of rapamycin (mTOR) [28].”
Epithelial–mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways (2005, methodology): “Bakin et al. showed that the dominant-negative N19 RhoA reduced AKT activation by TGFb, while a constitutively active mutant enhanced it, thus suggesting a role of RhoA upstream of PI3K/AKT (Bakin et al., 2000).”
Integration of TGF‐β/Smad and Jagged1/Notch signalling in epithelial‐to‐mesenchymal transition (2004, background): “…protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K), RhoA and Rac1 small GTPases, and Smads have all been implicated as mediators of some or all phenotypic aspects of TGF-b-induced EMT (Miettinen et al, 1994; Piek et al, 1999; Bakin et al, 2000; Bhowmick et al, 2001; Zavadil et al, 2001).”