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Key Signaling Pathways in Normal and Neoplastic Melanocytes

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Melanoma

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Abstract

Signal transduction pathways regulate the proliferation, differentiation, migration, and survival of melanocytes. These signaling pathways are dysregulated during the transformation of melanocytes, often due to somatic mutation of genes within the pathway. One major signaling pathway that highlights this paradigm is the mitogen-activated protein (MAP) kinase pathway. Growth factor signaling via the MAP kinase pathway is required for melanocyte proliferation and survival. MAP kinase signaling is activated in the majority of melanomas through somatic mutations in NRAS, BRAF, and MEK1/2. Regulation of proliferation and survival is also controlled by phosphatidyl-inositol 3′-kinase (PI3K) signaling. PI3K is a major regulator of melanocyte biology and is commonly activated through the mutation/loss of expression of negative not pathway regulators such as PTEN. Alterations in cyclin-dependent kinase signaling are also frequent in melanoma and promote aberrant cell cycle progression. Other pathways such as Gαq, Wnt (canonical and noncanonical), Hippo, Notch, and signaling downstream of Rho family GTPases also play important roles in the aforementioned biological processes, and in some cases are altered in selective subsets of melanoma. The high mutation burden within genes in signaling pathways, the important role of these pathways in melanocytic neoplasms, and the knowledge that melanomas adapt their signaling mechanisms in response to targeted inhibitors make it essential to have a thorough understanding of the key signaling pathways in melanocytes and melanomas.

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Acknowledgments

The Aplin Laboratory is supported by the NIH under award numbers: CA196278, CA160495 and CA182635, and by the Melanoma Research Alliance. The Weeraratna Laboratory is supported by NIH grants: CA174746, CA114046, CA207935, CA174523 and grants from the Melanoma Research Foundation and the Melanoma Research Alliance/L’Oreal.

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Authors and Affiliations

  1. Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    Andrew E. Aplin

  2. Melanoma Research Center, Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, PA, USA

    Ashani T. Weeraratna

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  1. Andrew E. Aplin
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  2. Ashani T. Weeraratna
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Correspondence to Andrew E. Aplin .

Editor information

Editors and Affiliations

  1. Harvard/MGH Cutaneous Biology Research C Massachusetts General Hospital, Boston, Massachusetts, USA

    David E. Fisher

  2. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Boris C. Bastian

Section Editor information

  1. Department of Dermatology, Harvard/MGH Cutaneous Biology Research Center, and Melanoma Program, MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    David E. Fisher

  2. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia

    Nick Hayward

  3. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia

    David C. Whiteman

  4. Henri and Belinda Termeer Center for Targeted Therapies, MGH Cancer Center, Boston, MA, USA

    Keith T. Flaherty

  5. Framingham, MA, USA

    F. Stephen Hodi

  6. Department of Medicine, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, MA, USA

    F. Stephen Hodi

  7. Auburndale, MA, USA

    Hensin Tsao

  8. Harvard-MIT Health Sciences and Technology, Cambridge, MA, USA

    Hensin Tsao

  9. Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Glenn Merlino

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Aplin, A.E., Weeraratna, A.T. (2018). Key Signaling Pathways in Normal and Neoplastic Melanocytes. In: Fisher, D., Bastian, B. (eds) Melanoma. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7322-0_26-1

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