Cutaneous malignant melanoma is one of the most serious skin cancers and is highly invasive and markedly resistant to conventional therapy. Melanomagenesis is initially triggered by environmental agents including ultraviolet (UV), which induces genetic/epigenetic alterations in the chromosomes of melanocytes. In human melanomas, the RAS/RAF/MEK/ERK (MAPK) and the PI3K/PTEN/AKT (AKT) signaling pathways are two major signaling pathways and are constitutively activated through genetic alterations. Mutations of RAF, RAS, and PTEN contribute to antiapoptosis, abnormal proliferation, angiogenesis, and invasion for melanoma development and progression. To find better approaches to therapies for patients, understanding these MAPK and AKT signaling mechanisms of melanoma development and progression is important. Here, we review MAPK and AKT signaling networks associated with melanoma development and progression. Cell signaling pathways are important for understanding not only cancer progression but also all life phenomena, including regulation of cell growth and death, migration, and angiogenesis [1–4]. Moreover, the events are accurately controlled by various intracellular signal transduction molecules [2, 5–7]. In cancer progression, the signaling is hyperactivated and/or silenced irreversibly. These irreversible losses of control in signal transduction allow cancers to acquire cancer-progression-specific phenotypes, such as antiapoptosis, abnormal proliferation, angiogenesis, and invasion. Previous studies revealed that collapse of signaling control was induced by both genetic and environmental factors [8–12]. Melanin-producing cells, acquired in several species from fungi to primates in the long evolutionary process, have many advantageous functions for survival strategy [13–19]. Melanocytes, melanin-producing cells that are the origin of melanoma, are developed from neural crest cells with several types of cell signaling pathways and gene expression [15, 20–22]. Human melanomas are categorized as nevus-associated melanomas and de novo melanomas based on their developmental process. Nevus-associated melanomas are transformants of preexisting benign lesions, and their malignant conversion progresses in a multistep manner [23–26]. De novo melanomas develop without pre-existing benign lesions [6, 27–29]. In humans, most melanomas are thought to have developed de novo. RFP-RET transgenic mice of line 304/B6 (RET mice) are powerful tools for analyses of melanoma with pre-existing benign lesions [6, 30, 31]. The entire process of melanoma development via
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