Growth factor-induced signaling of the pancreatic epithelium

Abstract

Activated signaling proteins regulate diverse processes, including the differentiation of the pancreatic islet cells during ontogeny. Here we uncover the in vivo phosphorylation status of major growth factor-activated signaling proteins in normal adult mice and during pancreatic islet regeneration. We report elevated phospho-mitogenactivated protein kinase (phospho-MAPK), phospho-cJun-NH 2 -terminal kinase (phospho-JNK), and phosphop38 MAPK expression during pancreatic regeneration. Immunoblotting experiments demonstrated elevated phosphorylation of p52 Src-homology/collagen (SHC) in the ductal network as well, substantiating the activation of this pathway. Furthermore, protein kinase B (PKB/Akt), a key signaling protein in the anti-apoptotic pathway, was phosphorylated to a greater extent in the ductal network from regenerating pancreas. We observed fibroblast growht factor (FGF)10 and platelet-derived growth factor (PDGF)AA expression in embryonic as well as regenerating adult pancreas. Epidermal growth factor (EGF) and PDGFAA stimulated MAPK and Akt phosphorylation, while FGF10 stimulated MAPK but not Akt phosphorylation in a time-dependent manner in freshly isolated cells from the adult ductal network. These data suggest that a heightened level of expression and stimulation of key signaling proteins underlie the expansion and differentiation processes that support pancreatic ontogeny and regeneration.

The role of the transcription factor ETV5 in insulin exocytosis

“…FGF10 and epidermal growth factor have been shown to play a role in pancreatic ontogeny and regeneration via the stimulation of mitogen-actvated protein kinase (MAPK) and Akt phosphorylation [21]. On the other hand, ETV5 is a target of MAPK [22], suggesting that ETV5 might be downstream of FGF10 signalling via MAPK activity.…”

Loss of Mitogen-Activated Protein Kinase Kinase Kinase 4 (MAP3K4) Reveals a Requirement for MAPK Signalling in Mouse Sex Determination

“…Interestingly, the insulin receptor tyrosine kinase gene family ( Ir , Igf1r , and Irr ) has previously been shown to be required for testis determination through its regulation of Sry expression [17], and a number of reports describe a requirement for MAPK in signal transduction through this family of receptors in different biological contexts [90],[91]. Similarly, loss of another RTK, PDGFRα, also disrupts testis development [21] and PDGF signalling is reported to employ MAPK [92]. Finally, in addition to RTK activity, prostaglandin D2 (PGD2) has been shown to influence Sertoli cell differentiation and SOX9 activity [39],[57],[58], presumably through its G-protein coupled receptors, DP and CRTH2 [93], although this is not established.…”

Exogenous FGF10 can rescue an eye‐open at birth phenotype of Fgf10‐null mice by activating activin and TGFα‐EGFR signaling

“…2003; Upadhyay et al . 2003; Kayali et al . 2005), FGF10 may activate the ERK pathway directly and/or via TGFα‐EGFR‐ERK during eyelid development in the mouse.…”