p21-Activated Kinase 4 Critically Regulates Melanogenesis via Activation of the CREB/MITF and β-Catenin/MITF Pathways

• Published in: Journal of investigative dermatology Vol. 135; no. 5; pp. 1385 - 1394
• Main Authors: Yun, Cheong-Yong, You, Soon-Tae, Kim, Jin-Hwa, Chung, Jin H., Han, Sang-Bae, Shin, Eun-Young, Kim, Eung-Gook
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2015
• Subjects: alpha-MSH - metabolism; Animals; beta Catenin - metabolism; Cell Line, Tumor; CREB-Binding Protein - metabolism; Dose-Response Relationship, Radiation; Humans; In Vitro Techniques; Melanins - metabolism; Melanocytes - drug effects; Melanocytes - metabolism; Melanocytes - radiation effects; Mice; Mice, Hairless; Microphthalmia-Associated Transcription Factor - metabolism; p21-Activated Kinases - antagonists & inhibitors; p21-Activated Kinases - metabolism; p21-Activated Kinases - pharmacology; Pyrazoles - pharmacology; Pyrroles - pharmacology; RNA Interference; Signal Transduction - drug effects; Signal Transduction - physiology; Signal Transduction - radiation effects; Ultraviolet Rays
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2014.548

p21-activated kinase 4 (PAK4) regulates a wide range of cellular events, including cytoskeletal remodeling, cell growth, and survival. Our previous study identified PAK4 as a key regulator of cAMP-response element–binding protein (CREB) that acts upstream of microphthalmia-associated transcription factor (MITF), a master transcription factor in melanogenesis. We therefore investigated the role of PAK4 in melanogenesis. Melanocytes express both PAK2 and PAK4 isoforms, but only RNA interference knockdown of PAK4 significantly influenced α-melanocyte-stimulating hormone (α-MSH)–induced melanogenesis in B16 melanoma cells. Consistent with this result, PAK4 inhibition by PF3758309, a potent ATP-competitive inhibitor of PAKs, suppressed not only α-MSH–induced melanogenesis in B16 melanoma and human epithelial melanocyte cells but also UVB-induced melanogenesis in the skin of melanin-possessing hairless mice (HRM-2) in a dose-dependent manner. Inhibition of PAK4 over several days markedly decreased the levels of CREB, MITF, and tyrosinase in both HRM-2 mice and B16 melanoma cells. Moreover, PAK4 knockdown and inhibition suppressed α-MSH-stimulated β-catenin phosphorylation at serine 675 (S675) but enhanced phosphorylation at S33/37, an indicator for ubiquitination-dependent proteolysis. Together, our results provide evidence that PAK4 promotes α-MSH/UVB-induced melanogenesis via the CREB and Wnt/β-catenin signaling pathways and suggest that PAK4 may be a potential therapeutic target in pigmentation disorders.