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Fig. 4 | Cell Communication and Signaling

Fig. 4

From: E-cadherin roles in animal biology: A perspective on thyroid hormone-influence

Fig. 4

T3-actions from genomic and non-genomic effects on cell adhesion and differentiation during vertebrate development. THs modulate energy metabolism, growth and development by independent mechanisms. While thyroid calorigenesis is influenced predominantly via nuclear receptors, many of the TH effects over development are thought to be mediated via cytosolic and membrane partners. E-cadherin trans-interaction triggers activation of the phosphatidylinositol-3-kinase (PI3K)–Akt–protein kinase B pathway bound to β-catenin, generating phosphatidylinositol-(3,4,5)-triphosphate (PIP3), recruitment of guanine nucleotide exchange factors, activation of Rac1 or Cdc42 and Akt, and reduction of Rho activation. In addition, TRα or TRβ forms a cytoplasmic complex with the p85 subunit of PI3K, inducing protein kinaseB/Akt nuclear translocation and inhibition of the Wnt/β-catenin pathway through its interaction and consequent sequestration of β-catenin. The process results in down-regulation of cell proliferation. Simultaneously, TH binding to TRs causes heterodimerization with retinoid X receptors (RXRs), binding to T3 response elements located within the genomic regions and shooting target gene transcription. In the absence of T3, TRs interact with co-repressor proteins to inhibit target gene transcription. Following T3 binding, co-repressors are displaced and co-activator proteins are recruited to the ligand-bound TR complex, facilitating T3-dependent activation of the target genes. Besides the TR-mediated functions, THs also exert rapid non-genomic actions that are initiated at the cell membrane. Integrin αvβ3 is a specific membrane receptor for THs, which mediate activation of the mitogen-activated protein kinase (MAPK) intracellular cascade. TH-dependent MAPK activation subsequently results in modulation of the membrane potential by regulation of ion channels, activation of the Na+/K+ exchanger and Ca2+ATPase, or regulation of actin cytoskeletal components anchored at the cell membrane. TH-activated MAPK, in turn, can rapidly translocate to the nucleus inducing serine phosphorylation of TRs, thereby resulting in the induction of angiogenesis or tumor cell proliferation. Nuclear targets for phosphorylated TRs include the transcription factors p53, STAT1a and STAT3

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