Developmental pathways activated in melanocytes and melanoma

Abstract

Cutaneous malignant melanomas originate primarily within epidermal melanocytic cells. Melanoma cells share many characteristics with melanocyte precursors, suggesting that melanoma cells utilize the developmental programs of their normal counterpart for their own progression. The pigmentation system provides an advantageous model to assess survival pathway interactions in the melanocytic lineage, as genetic alterations controlling melanocyte development can be easily detectable by coat color phenotype that do not affect the viability of an animal. By integrating combinatorial gene knockout approaches, cell-based assays and immunohistochemical observations, recent studies have illustrated several genes and pathways that play important roles both in melanocyte specification and maintenance and in melanoma formation and progression. We are reviewing those genes and pathways to understand the connection between normal and cancerous development and to reveal therapeutic potential of targeting developmental pathways for melanoma therapy.

Keywords: Beta-catenin; Endothelin; MITF; Melanocytes; Melanoma; Notch; Signaling pathways; Sox10; Sox9; Wnt.

Figure 1. Overview of Notch signaling pathway

The Notch receptor is translated as a full-length protein but it is cleaved in the trans-Golgi network into two subunits by furin-like convertases. After transport to the membrane, these subunits form the heterodimeric Notch receptor. The Notch signaling cascade is initiated upon binding of membrane-bound ligand (Jagged 1,2 and DSL 1,3,4) to the Notch receptors. Upon ligand binding two sequential proteolytic events occur to liberate active Notch Intracel- lular (NIC). The first cleavage is mediated by a metalloprotease, TNF-a-converting enzyme (TACE). The final cleavage is mediated by a γ-secretase complex. Subsequently, NIC translocates to the nucleus and functions as a transcription factor to influence gene expression including HES, Hey and other targets.

Figure 2. Canonical Wnt signaling

Wnt signaling is activated upon ligation of Wnt proteins to their respective dimeric cell surface receptors composed of the seven transmembrane Frizzled proteins and the LRP5/6. In the absence of Wnt ligand, β-catenin is not accumulating in the cytoplasm, as it is degraded by a destruction complex including Axin, adenomatosis polyposis coli (APC), protein phosphatase 2A (PP2A), glycogen synthase kinase 3 (GSK3) and casein kinase 1α (CK1α). In the presence of Wnt ligand, the cytoplasmic protein disheveled (Dvl) is recruited to the plasma membrane, phosphorylated and activated there. Activation of Dvl causes the dissociation of GSK-3β from Axin and leads to the inhibition of GSK-3β. Subsequently, the destruction complex is disrupted, and the phosphorylation and degradation of β-catenin is inhibited. Stabilized β-catenin then translocates into the nucleus leading to changes in different target gene expression.

Figure 3. Endothelin signaling pathway

Binding of endothelins to their receptors initiates a series of intracellular signal transduction events via heterotrimetic G-proteins. Activation of Ednr leads to the activation of phospholipase Cβ, inhibition of adenyl cyclase, activation of plasma membrane Ca2+ channels, and activation of non-receptor tyrosine kinases. In melanocytes, binding of Edn1 or Edn3 to Ednrb causes the activation of the pathways that include protein kinase C (PKC), mitogen-activated protein kinase (MAPK) and Raf-1.