Melanoma pp 63-81 | Cite as

Key Signaling Pathways in Normal and Neoplastic Melanocytes

  • Andrew E. AplinEmail author
  • Ashani T. Weeraratna
Reference work entry


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.


RAS BRAF ERK1/2 PI3K PTEN AKT GNAQ GNA11 Rac Rho PREX CDK4/6 Wnt β-catenin YAP TAZ Notch 



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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cancer Biology and Sidney Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Melanoma Research Center, Immunology, Microenvironment and MetastasisThe Wistar InstitutePhiladelphiaUSA

Section editors and affiliations

  • David E. Fisher
    • 1
  • Nick Hayward
    • 2
  • David C. Whiteman
    • 3
  • Keith T. Flaherty
    • 4
  • F. Stephen Hodi
    • 5
    • 6
  • Hensin Tsao
    • 7
    • 8
  • Glenn Merlino
    • 9
  1. 1.Department of Dermatology, Harvard/MGH Cutaneous Biology Research Center, and Melanoma Program, MGH Cancer CenterMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  2. 2.QIMR Berghofer Medical Research InstituteHerstonAustralia
  3. 3.QIMR Berghofer Medical Research InstituteHerstonAustralia
  4. 4.Henri and Belinda Termeer Center for Targeted TherapiesMGH Cancer CenterBostonUSA
  5. 5.FraminghamUSA
  6. 6.Department of Medicine, Brigham and Women's HospitalDana-Farber Cancer InstituteBostonUSA
  7. 7.AuburndaleUSA
  8. 8.Harvard-MIT Health Sciences and TechnologyCambridgeUSA
  9. 9.Center for Cancer ResearchNational Cancer InstituteBethesdaUSA

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