EGFR is involved in control of gastric cell proliferation through activation of MAPK and Src signalling pathways in early-weaned rats

Osaki, Luciana H.; Figueiredo, Priscila Moreira; Alvares, Eliana Parisi; Gama, Patrı́cia

doi:10.1111/j.1365-2184.2011.00733.x

Cited by 33 publications

(57 citation statements)

References 62 publications

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“…Moreover, we have previously shown that early weaning also influences the expression of growth factors and activation of signaling pathways. Accordingly, the abrupt change from milk to solid food modifies TGFβ3 localization [18], increases TGFα and EGFR protein levels [15], and stimulates ERK and Src phosphorylation in the gastric mucosa [20]. As mentioned before, early weaning stimulates gastric cell division [17], and such effect is reverted after the inhibition of EGFR phosphorylation [20], indicating that this receptor is part of the response.…”

Section: Introductionmentioning

confidence: 82%

MAPK Signaling Pathway Regulates p27 Phosphorylation at Threonin 187 as Part of the Mechanism Triggered by Early-Weaning to Induce Cell Proliferation in Rat Gastric Mucosa

Osaki

Gama

2013

PLoS ONE

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During rat postnatal development, gastric cell proliferation and differentiation depend on many elements, which include dietary pattern, hormones, growth factors and their signaling pathways. Among them, EGFR activity is increased through MAPK and Src cascades in response to early weaning that represents the abrupt transition from milk to solid food. We herein investigated the direct involvement of ERK pathway in the control of cell cycle progression during early weaning, and studied the specific role of p27. At 15 days, Wistar rats were separated from dams, fed with powdered chow and daily injected with PD98059 (MEK inhibitor, 300 µg/kg) or 0.5% DMSO (control). By using HE staining and immunohistochemistry for PCNA, we respectively detected mitotic (MI) and proliferative (PI) indices in 18-day-old pups, and observed that both were reduced by PD98059. As cell cycle-related proteins (cyclin E, CDK2, cyclin D1, CDK4, p21 and p27) are involved in proliferative regulation, we compared samples obtained at 17 days in the morning (17 d) and evening (17.5 d). We found that they were not altered after ERK inhibition, but cyclin D1, p21 and p27 levels changed throughout the day in the control group. As p27 activity depends on its integrity, we studied p27 phosphorylation (threonin 187), and observed that ERK inhibition reduced this process. We suggest that MAPK pathway interferes in the regulation of p27 function in the gastric mucosa during early weaning, possibly by controlling its degradation, and altogether this mechanism might contribute to the increase of epithelial proliferation at this condition.

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Section: Introductionmentioning

confidence: 82%

MAPK Signaling Pathway Regulates p27 Phosphorylation at Threonin 187 as Part of the Mechanism Triggered by Early-Weaning to Induce Cell Proliferation in Rat Gastric Mucosa

Osaki

Gama

2013

PLoS ONE

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“…Our finding that ERK is critical for inducing stem cell proliferation is consistent with other reports. In the juvenile rat, premature weaning also induces isthmal proliferation that depends on ERK signaling (63). In patients infected with H. pylori, it has been proposed that bacterial CagA activates the ERK cascade in gastric epithelial cells, which initiates the development of gastric cancer (64).…”

Section: Discussionmentioning

confidence: 99%

The Hyaluronic Acid Receptor CD44 Coordinates Normal and Metaplastic Gastric Epithelial Progenitor Cell Proliferation

Khurana

Riehl

Moore

et al. 2013

Journal of Biological Chemistry

105

106

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Background: Gastric parietal cell atrophy causes metaplasia, reactive stem cell proliferation, and increased risk for cancer. Results: Atrophy induces proliferation of CD44-positive epithelial cells that requires ERK 3 CD44 3 STAT3 signaling. Conclusion: CD44 is a putative gastric stem cell marker that regulates normal and metaplasia-associated proliferation. Significance: Targeted pharmacological inhibition of ERK/CD44/STAT3 signaling may help block or reverse proliferation in precancerous atrophic/metaplastic lesions.

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“…The EGF family of receptor-linked signals can be differentially regulated in different downstream pathways involved in cell proliferation and differentiation, including the Raf-MEK-ERK and AKT pathways (14,30). Despite evidence that AKT plays critical roles in cancer cell motility (19), the EGF receptor-ERK1/2 signaling cascade can be important in the regulation of multiple key biophysical processes underlying cell migration both in pathogenic and physiological states (18,25,35). In the present study, the blockade of the EGF receptor could not suppress the activated AKT signals, which implicates the EGF receptorindependent phosphorylation of AKT by the recombinant bacteria and their products.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Wound Healing by Recombinant Escherichia coli Nissle 1917 via Human Epidermal Growth Factor Receptor in Human Intestinal Epithelial Cells: Therapeutic Implication Using Recombinant Probiotics

Choi

Ahn²,

Park

et al. 2012

Infect Immun

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The gastrointestinal mucosa has a remarkable ability to repair damage with the support of epidermal growth factor (EGF), which stimulates epithelial migration and proliferative reepithelialization. For the treatment of mucosal injuries, it is important to develop efficient methods for the localized delivery of mucoactive biotherapeutics. The basic idea in the present study came from the assumption that an intestinal probiotic vehicle can carry and deliver key recombinant medicinal proteins to the injured epithelial target in patients with intestinal ulcerative diseases, including inflammatory bowel disease. The study was focused on the use of the safe probiotic E. coli Nissle 1917, which was constructed to secrete human EGF in conjunction with the lipase ABC transporter recognition domain (LARD). Using the in vitro physically wounded monolayer model, ABC transporter-mediated EGF secretion by probiotic E. coli Nissle 1917 was demonstrated to enhance the wound-healing migration of human enterocytes. Moreover, the epithelial wound closure was dependent on EGF receptor-linked activation, which exclusively involved the subsequent signaling pathway of the mitogen-activated protein kinase kinase (MEK) extracellular-related kinases 1 and 2 (ERK1/2). In particular, the migrating frontier of the wounded edge displayed the strongest EGF receptor-linked signaling activation in the presence of the recombinant probiotic. The present study provides a basis for the clinical application of human recombinant biotherapeutics via an efficient, safe probiotic vehicle.

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EGFR is involved in control of gastric cell proliferation through activation of MAPK and Src signalling pathways in early-weaned rats

Abstract: EGFR is part of the mechanism that regulates cell proliferation in rat gastric mucosa during early weaning. We suggest that such responses might depend on activation of MAPK and/or Src signalling pathways and regulation of p21 levels.

Cited by 33 publications

References 62 publications

MAPK Signaling Pathway Regulates p27 Phosphorylation at Threonin 187 as Part of the Mechanism Triggered by Early-Weaning to Induce Cell Proliferation in Rat Gastric Mucosa

MAPK Signaling Pathway Regulates p27 Phosphorylation at Threonin 187 as Part of the Mechanism Triggered by Early-Weaning to Induce Cell Proliferation in Rat Gastric Mucosa

The Hyaluronic Acid Receptor CD44 Coordinates Normal and Metaplastic Gastric Epithelial Progenitor Cell Proliferation

Enhanced Wound Healing by Recombinant Escherichia coli Nissle 1917 via Human Epidermal Growth Factor Receptor in Human Intestinal Epithelial Cells: Therapeutic Implication Using Recombinant Probiotics

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