Priority Research Papers:
Melanoma-associated mutants within the serine-rich domain of PAK5 direct kinase activity to mitogenic pathways
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Kyle M. LaPak1, Dennis C. Vroom1, Ayush A. Garg2, Xiangnan Guan1, John L. Hays3, Jonathan W. Song2 and Christin E. Burd1,4
1 Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA
2 Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH, USA
3 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA
4 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
Christin E. Burd, email: [email protected]
Keywords: PAK7; PKA; melanoma; melanocyte; p21-activated kinase
Received: April 01, 2018 Accepted: April 26, 2018 Published: May 22, 2018
The overexpression and hyperactivity of p21-activated serine/threonine kinases (PAKs) is known to facilitate tumorigenesis; however, the contribution of cancer-associated PAK mutations to tumor initiation and progression remains unclear. Here, we identify p21-activated serine/threonine kinase 5 (PAK5) as the most frequently altered PAK family member in human melanoma. More than 60% of melanoma-associated PAK5 gene alterations are missense mutations, and distribution of these variants throughout the protein coding sequence make it difficult to distinguish oncogenic drivers from passengers. To address this issue, we stably introduced the five most common melanoma-associated PAK5 missense mutations into human immortalized primary melanocytes (hMELTs). While expression of these mutants did not promote single-cell migration or induce temozolomide resistance, a subset of variants drove aberrant melanocyte proliferation. These mitogenic mutants, PAK5 S364L and D421N, clustered within an unstructured, serine-rich domain of the protein and inappropriately activated ERK and PKA through kinase-independent and -dependent mechanisms, respectively. Together, our findings establish the ability of mutant PAK5 to enhance PKA and MAPK signaling in melanocytes and localize the engagement of mitogenic pathways to a serine-rich region of PAK5.
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