Understanding the role of PAK7 mutations in melanoma
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Date
2017-05
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The Ohio State University
Abstract
Melanoma, the deadliest form of skin cancer, has a 5-year survival rate of 16% for patients diagnosed with advanced, highly disseminated disease (e.g. stage IV). Melanoma mortality is largely attributable to its metastatic potential. Thus, understanding the molecular mechanisms that drive melanoma metastasis is particularly important. p21 Activated Kinases (PAKs) are frequently altered in a variety of cancers and regulate mechanisms important for cancer development including: cell motility, proliferation, and apoptotic resistance. There are two groups of PAK proteins, which are based upon protein sequence homology: the group I PAKs consisting of PAKs 1, 2, and 3 and group II PAKs including PAKs 4, 6, and 7. PAK7 is the most frequently mutated PAK in melanoma; yet, the role of this protein in melanoma progression is unknown. Here, we tested the hypothesis that PAK7 mutants promote melanoma initiation and metastasis through the inappropriate activation of downstream signaling pathways. Human immortalized primary melanocytes stably expressing either melanoma- associated PAK7 mutants, kinase-dead, or kinase-hyperactive mutants were examined for alterations in proliferation, migration, and downstream signaling. In the absence of growth factors, some melanoma-associated PAK7 mutants (M173I, S364L, D421N) increased cellular proliferation while others (E144K) decreased motility. Additionally, some melanoma mutations showed changes in signaling through the mitogenic MAPK pathway. Immunoprecipitation of PAK7 was followed by mass spectrometry. This work identified GEF-H1, a guanine nucleotide exchange factor that activates Rho and Rac-GTPases, as a PAK7 interacting partner. As Rho and Rac-GTPases are both major players in cell motility, we validated the interaction between GEF-H1 and PAK7 in our melanocyte stable cell lines and discovered a correlation between increased PAK7 kinase activity and GEF-H1 phosphorylation. Together, this work suggests a model wherein PAK7 functions through GEF-H1 to influence cell motility. Future work will explore the role of PAK7-mediated GEF-H1 phosphorylation as a marker of human melanoma metastasis. Understanding the role of PAK7 in melanoma metastasis could lead to advances in diagnostic strategies to predict which melanomas are likely to metastasize and/or provide a novel therapeutic target by which metastasis could be slowed or prevented.
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Keywords
PAK7, melanoma