Fig. 8 | Nature Communications

Fig. 8

From: Olfactory receptor OR2AT4 regulates human hair growth

Fig. 8

Proposed mechanism of action of OR2AT4 activation by Sandalore® and (unknown) endogenous ligand(s) in human hair follicle epithelium. The activation of OR2AT4 at the cell surface of outer root sheath keratinocytes (ORS KCs; location: see green cells in the central HF cartoon) by endogenous ligands and/or Sandalore® upregulates the expression  of genes and kinases involved in programmed cell death, thus preventing intrafollicular apoptosis (e.g., by phosphorylation of PRAS40 preventing its interaction with mTOR1, upregulation of NF-κB pathway) or downregulates key players in the apoptotic machinery (e.g., dephosphorylation of p53, downregulation of Bad). In parallel, OR2AT4 activation by exogenous (Sandalore®) or endogenous ligands (e.g., metabolites of the HF microbiome) induces the upregulation of PAPPA that cleave the IGFBP4/IGF1 complex to release IGF-1 (pink arrows). The released IGF-1 triggers the activation of IGF-1R on the same cell (autocrine signaling, purple arrow) or on hair matrix keratinocytes (HM KCs; orange “cell”) (paracrine signaling, orange arrow). The activation of IGF-Rs on HM keratinocytes then induces signaling cascades (e.g., PI3K/AKT and/or p38a/ERK1/2/MSK1/2) that activate different transcription factors and particularly CREB, which results in an anti-apoptotic effect and prolonged anagen phase in human HFs. P phosphorylation, green square gene upregulation, red square gene downregulation, green circle phosphorylation, red circle dephosphorylation

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