An ErbB receptor–mediated AP‐1 regulatory network is modulated by STAT3 and c‐MYC during calcium‐dependent keratinocyte differentiation

Abstract

A calcium gradient in skin epidermis is known to regulate epidermal differentiation. In cultures of human epidermal keratinocytes (NHEK), induction of calcium-dependent differentiation is associated with phosphorylation of ErbB receptors, including the epidermal growth factor receptor (EGFR). The activation of EGFR triggers the induction of activator protein 1 (AP-1) proteins necessary for keratinocyte terminal differentiation. Interestingly, an in vitro long-term calcium treatment revealed the activation of different ErbB receptors with different timings, which is consistent with the differential localization of each receptor in the skin layers in vivo. In the current study, the regulatory relationship between ErbB receptor activation and induction of AP-1 proteins in calcium-dependent keratinocyte differentiation was analysed. For this purpose, we used a mathematical method to predict molecular regulations from time-course proteomic data of 30 target components. The predicted network showed that the ErbB receptor might regulate AP-1 protein expression via two pathways: positive regulation by c-MYC and negative regulation by signal transducer and activator of transcription 3 (STAT3) pathways. Experimental validation analysis revealed that ErbB receptor inhibition resulted in defective induction of AP-1 proteins and suppressed terminal differentiation of keratinocytes. Inhibition of STAT3, however, affected expression of a partial set of AP-1 proteins and resulted in premature differentiation. Studies using RNAi to diminish expression of each ErbB receptor and the AP-1 proteins strongly suggested that STAT3 established a balance that maintains the appropriate set of AP-1 proteins and participates in a complex network for regulating keratinocyte differentiation.

Six1 overexpression at early stages of HPV16-mediated transformation of human keratinocytes promotes differentiation resistance and EMT

“…7B). Signal transducer and activator of transcription 3 (STAT3) also plays an important role in differentiation, migration and apoptosis of keratinocytes (Saeki et al, 2012). The phosphorylation of STAT3 increased in HKc/HPV16-Six1 compared to HKc/HPV16-Ctrl (Fig.…”

“…Constitutive activation of STAT3 in mouse epidermis results in partial loss of the keratinocyte differentiation markers K10 and filaggrin and enhances malignant progression (Chan et al, 2008). STAT3 knock-down sensitizes terminal differentiation of HKc at low-calcium condition (Saeki et al, 2012). Our study showed a significant activation of STAT3 in Six1-overexpressing HKc/HPV16.…”

Ligand‐independent epidermal growth factor receptor hyperactivation increases sebaceous gland size and sebum secretion in mice

“…First, c-myc is a target gene of MAPK, a major signalling pathway downstream of the EGFR (13), and EGF was shown to stimulate c-myc expression in keratinocytes (14,15). Second, c-myc emerged as the major pathway mediating EGFR/ERBB signalling in keratinocytes (16). Third, c-myc overexpression in the skin of transgenic mice promoted SG enlargement accompanied by increased cell proliferation (17)(18)(19), and increased c-myc levels were associated with enhanced cell proliferation and enlarged SGs in Blimp1-deficient mice (20).…”

Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3‐Ser727 phosphorylation as a modulator of transcriptional activity

“…Several studies have implicated STAT3 in regulating fundamental cellular biological processes such as proliferation, differentiation, malignant transformation, survival and apoptosis . Total STAT3 expression has also been proven to be upregulated in psoriatic lesions and a transgenic mouse model constitutively overexpressing activated STAT3 in the basal stem‐cell layer of the epidermis was able to reproduce many of the characteristic features of psoriasis .…”