BACKGROUNDS/AIMS: Insulin receptor substrate-4 (IRS-4) is a scaffold protein that mediates the actions of insulin-like growth factor-I (IGF-I). Its expression increases dramatically after partial hepatectomy (a liver regeneration model). Herein, we report IRS-4 expression in a human hepatoblastoma cell line (HepG2) and IGF-I-dependent IRS-4 tyrosine phosphorylation. METHODS: The role of IRS-4 in HepG2 proliferation was established by RNA interference (siRNA). After 72h of transfection with IRS-4 siRNA, we observed a specific reduction in IRS-4 expression. RESULTS: Depletion of IRS-4 levels decreased ERK phosphorylation, p70S6K phosphorylation and IGF-I-stimulated cell proliferation. Changes in ERK phosphorylation in IRS-4-depleted cells were independent of ras/raf/MEK1/2- and PI3K/Akt-cascades. IRS-4 down-regulation abolished IGF-I-, TPA- and IGF-I plus TPA-stimulated ERK and p70S6K activities. Our results suggest that PKC-epsilon mediates the effect of IRS-4 on ERK activity. Moreover, decreased IRS-4 levels diminished FBS- and IGF-I-stimulated HepG2 growth and cause stress fiber disruption in HepG2 cell line. CONCLUSIONS: Collectively, our data suggest that IRS-4 plays an important role in HepG2 proliferation/differentiation and exerts its actions through ERK and p70S6K activation in a ras/raf/MEK1/2- and PI3Kinase/Akt-independent manner and in a PKC-dependent way.
BACKGROUNDS/AIMS: Insulin receptor substrate-4 (IRS-4) is a scaffold protein that mediates the actions of insulin-like growth factor-I (IGF-I). Its expression increases dramatically after partial hepatectomy (a liver regeneration model). Herein, we report IRS-4 expression in a humanhepatoblastoma cell line (HepG2) and IGF-I-dependent IRS-4tyrosine phosphorylation. METHODS: The role of IRS-4 in HepG2 proliferation was established by RNA interference (siRNA). After 72h of transfection with IRS-4 siRNA, we observed a specific reduction in IRS-4 expression. RESULTS: Depletion of IRS-4 levels decreased ERK phosphorylation, p70S6K phosphorylation and IGF-I-stimulated cell proliferation. Changes in ERK phosphorylation in IRS-4-depleted cells were independent of ras/raf/MEK1/2- and PI3K/Akt-cascades. IRS-4 down-regulation abolished IGF-I-, TPA- and IGF-I plus TPA-stimulated ERK and p70S6K activities. Our results suggest that PKC-epsilon mediates the effect of IRS-4 on ERK activity. Moreover, decreased IRS-4 levels diminished FBS- and IGF-I-stimulated HepG2 growth and cause stress fiber disruption in HepG2 cell line. CONCLUSIONS: Collectively, our data suggest that IRS-4 plays an important role in HepG2 proliferation/differentiation and exerts its actions through ERK and p70S6K activation in a ras/raf/MEK1/2- and PI3Kinase/Akt-independent manner and in a PKC-dependent way.
Authors: Patricia Sanmartín-Salinas; M Val Toledo-Lobo; Fernando Noguerales-Fraguas; María-Encarnación Fernández-Contreras; Luis G Guijarro Journal: J Mol Histol Date: 2017-11-28 Impact factor: 2.611
Authors: Patricia Sanmartín-Salinas; María Del Val Toledo Lobo; Fernando Noguerales-Fraguas; Miguel Toro Londoño; Antonio Jiménez-Ruiz; Luis Gonzalez Guijarro Journal: J Gastroenterol Date: 2018-01-20 Impact factor: 7.527
Authors: Borja Hernández-Breijo; Jorge Monserrat; Sara Ramírez-Rubio; Eva P Cuevas; Diana Vara; Inés Díaz-Laviada; M Dolores Fernández-Moreno; Irene D Román; Javier P Gisbert; Luis G Guijarro Journal: World J Gastroenterol Date: 2011-09-14 Impact factor: 5.742
Authors: Luis G Guijarro; Patricia Sanmartin-Salinas; Eva Pérez-Cuevas; M Val Toledo-Lobo; Jorge Monserrat; Sofía Zoullas; Miguel A Sáez; Miguel A Álvarez-Mon; Julia Bujan; Fernando Noguerales-Fraguas; Eduardo Arilla-Ferreiro; Melchor Álvarez-Mon; Miguel A Ortega Journal: Cancers (Basel) Date: 2021-05-23 Impact factor: 6.639