Role of FGFR2b expression and signaling in keratinocyte differentiation: sequential involvement of PKCδ and PKCα

Rosato, Benedetta; Ranieri, Danilo; Torrisi, Maria Rosaria; Belleudi, Francesca

doi:10.1038/s41419-018-0509-x

Cited by 16 publications

(15 citation statements)

References 51 publications

(93 reference statements)

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“…The phosphorylation of PKCδ at the autophosphorylation site Serine 645, which belongs to the characteristic phosphorylation pattern of PKCδ activation [19] was observed in all clones only in response to FGF7 (Fig. 1a), was in agreement with our recent data proposing a key role of this PKC family member in the early steps of FGF7-mediated keratinocyte differentiation [7]. No evident modulation of both PKCδ protein ( Fig.…”

Section: Pkcε Signaling Is Responsible For Fgfr2c-mediated Modulationsupporting

confidence: 91%

“…In this regard, several studies have demonstrated that the switching from the epithelial isoforms of fibroblast growth factor receptors (FGFR1-3b) to the mesenchymal FGFR1-3c isoforms is frequently involved in epithelialmesenchymal transition (EMT) and cancer progression [2][3][4]. In the last years we focused our attention on the biological functions of the epithelial FGFR2b isoform, demonstrating that this receptor controls the entire program of keratinocyte differentiation [5][6][7] through the sequential involvement of PKCδ and PKCα signaling [7]. In contrast, we found that the FGFR2 isoform switch and the aberrant expression of the mesenchymal FGFR2c isoform in the same epidermal context induced changes in FGFR ligand specificity, leading to impairment of differentiation [8], EMT and early tumorigenic features [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Role of PKCε in the epithelial-mesenchymal transition induced by FGFR2 isoform switch

et al. 2020

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Background: The epithelial isoform of the fibroblast growth factor receptor 2 (FGFR2b) controls the entire program of keratinocyte differentiation via the sequential involvement of protein kinase C (PKC) δ and PKCα. In contrast, the FGFR2 isoform switch and the aberrant expression of the mesenchymal FGFR2c isoform leads to impairment of differentiation, epithelial-mesenchymal transition (EMT) and tumorigenic features. Aim of our present study was to contribute in clarifying the complex network of signaling pathways involved in the FGFR2c-mediated oncogenic outcomes focusing on PKCε, which appears to be involved in the induction of EMT and tumorigenesis in several epithelial contexts. Methods: Biochemical and molecular analysis, as well as in vitro invasion assays, combined with the use of specific small interfering RNA (siRNA), were performed in human keratinocytes stably expressing FGFR2c or FGFR2b isoforms. Results: Our results showed that aberrant expression and signaling of FGFR2c, but not those of FGFR2b, in human keratinocytes induced a strong phosphorylation/activation of PKCε. The use of siRNA approach showed that PKCε is the hub signaling downstream FGFR2c responsible for the modulation of EMT markers and for the induction of the EMT-related transcription factors STAT3, Snail1 and FRA1, as well as for the acquisition of the invasive behavior. Moreover, experiments of depletion of ESRP1, responsible for FGFR2 splicing in epithelial cells, indicated that the activation of PKCε is the key molecular event triggered by FGFR2 isoform switch and underlying EMT induction. Conclusions: Overall, our results point to the identification of the downstream PKC isoform responsible for the FGFR signaling deregulation occurring in epithelial tissues from the physiological oncosoppressive to the pathological oncogenic profile.

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Section: Pkcε Signaling Is Responsible For Fgfr2c-mediated Modulationsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Role of PKCε in the epithelial-mesenchymal transition induced by FGFR2 isoform switch

et al. 2020

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“…Concerning Fibroblast Growth Factor Receptors (FGFRs), several findings strongly suggested that the dysregulation of FGFR expression and signaling could also contribute to AK pathogenesis [ 10 , 11 , 12 ]. This possibility is also sustained by our recent observations, demonstrating that, while the epithelial isoform of FGFR2 (FGFR2b) is directly implicated in keratinocyte differentiation [ 13 ], the altered FGFR2 isoform switching and the consequent aberrant expression of the mesenchymal FGFR2c isoform in human keratinocytes induce changes in FGF specificity, leading to impairment of differentiation [ 14 ] and induction of EMT and tumorigenic features [ 15 , 16 ]. Even if our findings are consistent with the opposite oncogenic and tumor-suppressive roles previously proposed for FGFR2c and FGFR2b, respectively [ 17 , 18 , 19 ], the specific function of each FGFR2 isoform in carcinogenesis, and in particular their role during the progression of pre-malignant lesions, such as AK, remains to be further clarified.…”

Section: Introductionmentioning

confidence: 69%

Expression Profile of Fibroblast Growth Factor Receptors, Keratinocyte Differentiation Markers, and Epithelial Mesenchymal Transition-Related Genes in Actinic Keratosis: A Possible Predictive Factor for Malignant Progression?

Persechino

Ranieri

Guttieri

et al. 2021

Biology

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Actinic keratosis (AK) is the ultra violet (UV)-induced preneoplastic skin lesion clinically classified in low (KIN I), intermediate (KIN II), and high (KIN III) grade lesions. In this work we analyzed the expression of Fibroblast Growth Factor Receptors (FGFRs), as well as of keratinocyte differentiation and epithelial-to-mesenchymal transition (EMT)-related markers in differentially graded AK lesions, in order to identify specific expression profiles that could be predictive for direct progression of some KIN I lesions towards squamous cell carcinoma (SCC). Our molecular analysis showed that the keratinocyte differentiation markers keratin 1 (K1), desmoglein-1 (DSG1), and filaggrin (FIL) were progressively downregulated in KIN I, II, and III lesions, while the modulation of epithelial/mesenchymal markers and the induction of the transcription factors Snail1 and Zinc finger E-box-binding homeobox 1 (ZEB1) compatible with pathological EMT, even if observable, did not appear to correlate with AK progression. Concerning FGFRs, a modulation of epithelial isoform of FGFR2 (FGFR2b) and the mesenchymal FGFR2c isoform compatible with an FGFR2 isoform switch, as well as FGFR4 upregulation were observed starting from KIN I lesions, suggesting that they could be events involved in early steps of AK pathogenesis. In contrast, the increase of FGFR3c expression, mainly appreciable in KIN II and KIN III lesions, suggested a correlation with AK late progression. Interestingly, the strong modulation of FIL, Snail1, as well as of FGFR2c, FGFR4, and of their ligand FGF2, observed in some of the KIN I samples, may indicate that they could be molecular markers predictive for those low graded lesions destined to a direct progression to SCC. In conclusion, our data point on the identification of molecular markers predictive for AK rapid progression through the “differentiated” pathway. Our results also represent an important step that, in future, will help to clarify the molecular mechanisms underlying FGFR signaling deregulation in epithelial tissues during the switch from the pre-neoplastic to the oncogenic malignant phenotype.

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“…In this regard, the epithelial isoform of FGFR2 (FGFR2b) is a well-recognized regulator of epidermal differentiation and skin homeostasis [5,6,7] exerting a tumor suppressive role in vitro and in vivo [8,9]. According to these studies, our group has demonstrated that FGFR2b controls the entire program of human keratinocyte differentiation [10,11,12] and that PKCδ and PKCα signaling downstream FGFR2b are involved in different steps of this process [12]. However, we also found that, in the same epidermal tissue context, the altered FGFR2 splicing and the aberrant expression of the mesenchymal FGFR2c isoform induces changes in the specificity for FGFs, leading to impairment of differentiation [13], epithelial mesenchymal transition (EMT) and early tumorigenic features [14].…”

Section: Introductionmentioning

confidence: 99%

The Aberrant Expression of the Mesenchymal Variant of FGFR2 in the Epithelial Context Inhibits Autophagy

Ranieri

Persechino

Torrisi

et al. 2019

Cells

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Signaling of the epithelial splice variant of fibroblast growth factor receptor 2 (FGFR2b) triggers both differentiation and autophagy, while the aberrant expression of the mesenchymal FGFR2c isoform in epithelial cells induces impaired differentiation, epithelial mesenchymal transition (EMT) and tumorigenic features. Here we analyzed in the human keratinocyte cell line, as well as in primary cultured cells, the possible impact of FGFR2c forced expression on the autophagic process. Biochemical and quantitative immunofluorescence analysis, coupled to the use of autophagic flux sensors, specific substrate inhibitors or silencing approaches, showed that ectopic expression and the activation of FGFR2c inhibit the autophagosome formation and that AKT/MTOR is the downstream signaling mainly involved. Interestingly, the selective inhibition of AKT or MTOR substrates caused a reversion of the effects of FGFR2c on autophagy, which could also arise from the imbalance of the interplay between AKT/MTOR pathway and JNK1 signaling in favor of JNK1 activation, BCL-2 phosphorylation and possibly phagophore nucleation. Finally, silencing experiments of depletion of ESRP1, responsible for FGFR2 splicing and consequent FGFR2b expression, indicated that the switching from FGFR2b to FGFR2c isoform could represent the key event underlying the inhibition of the autophagic process in the epithelial context. Our results provide the first evidence of a negative impact of the out-of-context expression of FGFR2c on autophagy, suggesting a possible role of this receptor in the modulation of the recently proposed negative loop between autophagy and EMT during carcinogenesis.

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Role of FGFR2b expression and signaling in keratinocyte differentiation: sequential involvement of PKCδ and PKCα

Cited by 16 publications

References 51 publications

Role of PKCε in the epithelial-mesenchymal transition induced by FGFR2 isoform switch

Role of PKCε in the epithelial-mesenchymal transition induced by FGFR2 isoform switch

Expression Profile of Fibroblast Growth Factor Receptors, Keratinocyte Differentiation Markers, and Epithelial Mesenchymal Transition-Related Genes in Actinic Keratosis: A Possible Predictive Factor for Malignant Progression?

The Aberrant Expression of the Mesenchymal Variant of FGFR2 in the Epithelial Context Inhibits Autophagy

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