The Receptor Tyrosine Kinase FGFR2b/KGFR Controls Early Differentiation of Human Keratinocytes

Abstract

The FGFRs trigger divergent responses, such as proliferation and differentiation, and the cell type as well as the context-dependent signaling are crucial for the functional outcome. The FGFR2b/KGFR is expressed exclusively on epithelial cells and plays a key role in skin homeostasis. Here we analyzed in vitro the role of KGFR in the early differentiation of keratinocytes modulating its expression by KGFR cDNA transient transfection or KGFR siRNA microinjection and inducing a synchronous wave of differentiation in pre-confluent cells. Immunofluorescence, biochemical and molecular approaches demonstrated that KGFR overexpression increased the early differentiation marker keratin 1 at both transcriptional and translational levels, while receptor depletion reduced it. Ligand-dependent receptor activation and signaling were required for this differentiative effect. Overexpression of kinase negative KGFR mutant or Tyr769 KGFR signaling mutant, which is not able to recruit and activate PLC-γ, showed that the receptor kinase activity, but not its PLCγ-mediated signaling, is required for differentiation. Reduction of K1 expression, obtained by AKT inhibition, demonstrated that the PI3K/Akt signaling pathway is involved in the control of KGFR-mediated keratinocyte differentiation. This in vitro experimental model indicates that FGFR2b/KGFR expression represents a key event regulating keratinocyte early differentiation during the switch from undifferentiated to differentiating cells.

FGF7/KGF regulates autophagy in keratinocytes

“…The possible crucial role of FGF7 and its receptor in epithelial cell homeostasis has been widely proposed 25 - 27 . In particular, we have recently demonstrated that the FGF7-mediated activation of FGFR2 triggers early differentiation in keratinocytes during the switch from undifferentiated to differentiating cells, 28 the same step in which it has been recently proposed that autophagy might represent a crucial event for cell commitment to differentiation 29 . Moreover, FGFR2 expression and signaling regulate the phagocytic process in keratinocytes 30 .…”

Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC

“…p38-MAPK regulates a wide range of targets, including other kinases/phosphatases, transcription factors and RNA-binding proteins (Cuadrado and Nebreda, 2010). Moreover, p38-MAPK is a downstream target of FGFR2b, a crucial receptor for epithelial differentiation in the skin and prostate (Belleudi et al, 2011;Heer et al, 2006;Lamb et al, 2010). Despite these findings, how p38-MAPK expression in prostate epithelial cells drives differentiation, including its relevant targets, remains poorly defined.…”

“…This results in a stratified epithelium consisting of suprabasal luminal cells sitting on top of basal cells. p38-MAPK is a known downstream target of KGF-to-FGFR2 signaling and is implicated in epithelial differentiation in several tissue types, including prostate (Belleudi et al, 2011;Lamb et al, 2010). Four different genes encode p38-MAPK isoforms: MAPK14 ( p38α), MAPK11 ( p38β), MAPK12 ( p38γ) and MAPK13 ( p38δ).…”

Progress in Relevant Growth Factors Promoting the Growth of Hair Follicle

“…It is supposed to be secreted from fibroblasts mainly in the stroma and bind to KGF Receptor (KGFR), which has been detected only on the surface of epithelial cells (Lin et al, 2010). KGFR still exists in hair follicles and is expressed in hair follicle epithelial cells and KGF in dermal papilla cells, which declares that KGF is mediated through paracrine (Belleudi et al, 2011). Koria et al (2011) showed KGF was expressed in normal skin and was induced upon injury.…”