Melanocyte-keratinocyte_interactions.jpg (600 × 416 pixels, file size: 96 KB, MIME type: image/jpeg)
Simplified schematic showing of key molecules and signaling pathways implicated in melanocyte-keratinocyte interactions.
In the melanocyte lineage, a series of transcription factors, including Pax3, Sox10, Creb, Lef1, and Mitf play crucial roles in the regulation of melanocyte proliferation, differentiation, and survival. Expression the melanocyte master regulatory gene Mitf is regulated by synergistic action of Pax3, Sox10, Lef1, and Creb on its promoter/enhancer. Mitf activates its own promoter by positive feedback loop. Once translated, Mitf protein is phosphorylated by the Erk kinase downstream activation of c-Kit signaling pathway. Phosphorylation of Mitf results in stabilization of Mitf-p300 transactivation complex, and thereby upregulating its transcriptional activity to stimulate expression of the target genes including Dct, Typ, and Tyrp1. c-Kit signaling also stimulates expression of Bcl2 to mediate melanocyte survival. Activation of melanocortin signaling pathway increases cytoplasmic cAMP concentration, which results in activation of CREB. This activated CREB directly binds the cAMP-responsive elements present on the promoter regions of Mitf and various melanosomal genes, and stimulates their gene expressions. Wnt signaling is required for melanocyte development. Activation of Wnt signaling results in the stabilization of β-catenin/Lef complex, which leads in transactivation of downstream target genes such as Mitf to promote melanocyte-fate specification and melanocyte differentiation. In contrast, keratinocyte expression of TGF-β plays a role in suppressing melanogenesis. Activation of TGF-β signaling results in the repression of Pax3 through phosphorylated Smads, which leads to Mitf repression to block melanocyte activation. Activation of Notch signaling is essential for the survival of melanoblasts, while underlying molecular mechanism is unclear. pSmad, phosphorylated Smads; Fzd, Frizzeled; cAMP, adenosine 3′:5′-cyclic monophosphate; CREB, cAMP responsive element binding protein, Pkc protein kinase C; Erk, extracellular signal-regulated kinase/mitogen-activated protein kinase, and pMitf, phosphorylated Mitf. Signaling molecules and transcription factors whose physiological roles in melanocytes are evidenced by genetic mutant animals are shown in red.
Figure 3 Osawa03.jpg
From: Melanocyte stem cells
Copyright: © 2009 Masatake Osawa.
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|current||18:45, 16 May 2011||600 × 416 (96 KB)||S8600021||Simplified schematic showing of key molecules and signaling pathways implicated in melanocyte-keratinocyte interactions. In the melanocyte lineage, a series of transcription factors, including Pax3, Sox10, Creb, Lef1, and Mitf play crucial roles in the r|