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Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
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Melanoma-associated mutants within the serine-rich domain of PAK5 direct kinase activity to mitogenic pathways

Kyle M LaPak1, Dennis C Vroom1, Ayush A Garg2

  • 1Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA.

Oncotarget
|June 8, 2018
PubMed

Insights

Mutant p21-activated serine/threonine kinase 5 (PAK5) drives melanoma cell proliferation by activating ERK and PKA signaling pathways. These findings highlight specific PAK5 mutations as potential drivers of melanoma development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Overexpression and hyperactivity of p21-activated serine/threonine kinases (PAKs) are implicated in tumorigenesis.
  • The specific role of cancer-associated PAK mutations in tumor initiation and progression is not fully understood.

Purpose of the Study:

  • To investigate the contribution of melanoma-associated p21-activated serine/threonine kinase 5 (PAK5) mutations to tumor development.
  • To identify the mechanisms by which mutant PAK5 influences melanocyte behavior and signaling pathways.

Main Methods:

  • Identified PAK5 as the most frequently altered PAK family member in human melanoma.
  • Introduced five common melanoma-associated PAK5 missense mutations into human immortalized primary melanocytes (hMELTs).
  • Assessed the impact of these mutations on melanocyte proliferation, migration, and drug resistance, as well as their effects on ERK and PKA signaling.

Main Results:

  • While not affecting single-cell migration or temozolomide resistance, a subset of PAK5 mutants (S364L and D421N) induced aberrant melanocyte proliferation.
  • These mitogenic mutants activated ERK (kinase-independent) and PKA (kinase-dependent) signaling.
  • The mutations were localized to a serine-rich domain of PAK5, suggesting this region is critical for mitogenic pathway engagement.

Conclusions:

  • Mutant PAK5 can promote melanocyte proliferation, suggesting a role in melanoma initiation and progression.
  • PAK5 mutations enhance PKA and MAPK signaling pathways through both kinase-dependent and -independent mechanisms.
  • A serine-rich region within PAK5 is identified as a key site for the engagement of mitogenic pathways by oncogenic mutations.
Keywords:
PAK7PKAmelanocytemelanomap21-activated kinase

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