scholarly journals Stimulation of Insulin-Like Growth Factor (IGF) Binding Protein-3 Synthesis by IGF-I and Transforming Growth Factor-α Is Mediated by Both Phosphatidylinositol-3 Kinase and Mitogen-Activated Protein Kinase Pathways in Mammary Epithelial Cells

Endocrinology ◽  
2004 ◽  
Vol 145 (9) ◽  
pp. 4213-4221 ◽  
Author(s):  
Usha Sivaprasad ◽  
Jodie Fleming ◽  
Poonam S. Verma ◽  
Kelly A. Hogan ◽  
Gwenaëlle Desury ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Mitogen Activated Protein Kinase ◽  
Transforming Growth Factor Α ◽  
Mitogen Activated Protein ◽  
Igf Binding ◽  
Factor Α ◽  
Igf Binding Protein

scholarly journals Metalloproteinases and Transforming Growth Factor-α Mediate Substance P-induced Mitogen-activated Protein Kinase Activation and Proliferation in Human Colonocytes

2004 ◽  
Vol 279 (44) ◽  
pp. 45519-45527 ◽  
Author(s):  
Hon-Wai Koon ◽  
Dezheng Zhao ◽  
Xi Na ◽  
Mary P. Moyer ◽  
Charalabos Pothoulakis
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Chronic Colitis ◽  
Transforming Growth Factor Α ◽  
Egfr Ligands ◽  
Mitogen Activated Protein ◽  
Factor Α

Substance P (SP) participates in acute intestinal inflammation via binding to the G-protein-coupled neurokinin-1 receptor (NK-1R) and release of proinflammatory cytokines from colonic epithelial cells. SP also stimulates cell proliferation, a critical event in tissue healing during chronic colitis, via transactivation of the epidermal growth factor (EGF) receptor (EGFR) and activation of mitogen-activated protein kinase (MAPK). Here we examined the mechanism by which SP induces EGFR and MAPK activation. We used non-transformed human NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) as well as untransfected U373 MG cells expressing high levels of endogenous NK-1R. Exposure of both cell lines to SP (10–7m) stimulated EGFR activation (1 min) followed by extracellular signal-regulated protein kinase (ERK1/2) activation (2–5 min). SP-induced ERK1/2 activation was blocked by pretreatment with the metalloproteinase inhibitor Batimastat/GM6001, the EGFR phosphorylation inhibitor AG1478, and the tumor necrosis factor-α-converting enzyme (TACE) inhibitor TAPI-1. Pretreatment with antibodies against potential EGFR ligands suggested that transforming growth factor-α (TGFα), but not the other EGFR ligands EGF, heparin-binding EGF, or amphiregulin, mediates SP-induced EGFR transactivation. SP stimulated TGFα release into the extracellular space that was measurable within 2 min, and this release was inhibited by metalloproteinase inhibitors and the TACE inhibitor TAPI-1. SP also induced MAPK-mediated cell proliferation that was inhibited by TACE, matrix metalloproteinase (MMP), EGFR, and MEK1 inhibitors. Thus, in human colonocytes, NK-1R-induced EGFR and MAPK activation and cell proliferation involve matrix metalloproteinases (most likely TACE) and the release of TGFα. These signaling mechanisms may be involved in the protective effects of NK-1R in chronic colitis.

scholarly journals Cripto-1 Activates Nodal- and ALK4-Dependent and -Independent Signaling Pathways in Mammary Epithelial Cells

2002 ◽  
Vol 22 (8) ◽  
pp. 2586-2597 ◽  
Author(s):  
Caterina Bianco ◽  
Heather B. Adkins ◽  
Christian Wechselberger ◽  
Masaharu Seno ◽  
Nicola Normanno ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Signaling Pathways ◽  
Family Member ◽  
Transforming Growth Factor ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Mitogen Activated Protein Kinase ◽  
Type I

ABSTRACT Cripto-1 (CR-1), an epidermal growth factor-CFC (EGF-CFC) family member, has a demonstrated role in embryogenesis and mammary gland development and is overexpressed in several human tumors. Recently, EGF-CFC proteins were implicated as essential signaling cofactors for Nodal, a transforming growth factor β family member whose expression has previously been defined as embryo specific. To identify a receptor for CR-1, a human brain cDNA phage display library was screened using CR-1 protein as bait. Phage inserts with identity to ALK4, a type I serine/threonine kinase receptor for Activin, were identified. CR-1 binds to cell surface ALK4 expressed on mammalian epithelial cells in fluorescence-activated cell sorter analysis, as well as by coimmunoprecipitation. Nodal is coexpressed with mouse Cr-1 in the mammary gland, and CR-1 can phosphorylate the transcription factor Smad-2 in EpH-4 mammary epithelial cells only in the presence of Nodal and ALK4. In contrast, CR-1 stimulation of mitogen-activated protein kinase and AKT in these cells is independent of Nodal and ALK4, suggesting that CR-1 may modulate different signaling pathways to mediate its different functional roles.

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