p21-activated kinase 4 critically regulates melanogenesis via activation of the CREB/MITF and β-catenin/MITF pathways.

Abstract

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.

• Authors: Cheong-Yong Yun, Soon-Tae You, Jin-Hwa Kim, Jin H Chung, Sang-Bae Han, Eun-Young Shin, Eung-Gook Kim
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 135 Issue 5 Pg. 1385-1394 (May 2015) ISSN: 1523-1747 [Electronic] United States
• PMID: 25560280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Melanins
• Microphthalmia-Associated Transcription Factor
• Mitf protein, mouse
• PF 3758309
• Pyrazoles
• Pyrroles
• beta Catenin
• alpha-MSH
• CREB-Binding Protein
• Crebbp protein, mouse
• Pak4 protein, mouse
• p21-Activated Kinases

Topics

• Animals
• CREB-Binding Protein (metabolism)
• Cell Line, Tumor
• Dose-Response Relationship, Radiation
• Humans
• In Vitro Techniques
• Melanins (metabolism)
• Melanocytes (drug effects, metabolism, radiation effects)
• Mice
• Mice, Hairless
• Microphthalmia-Associated Transcription Factor (metabolism)
• Pyrazoles (pharmacology)
• Pyrroles (pharmacology)
• RNA Interference
• Signal Transduction (drug effects, physiology, radiation effects)
• Ultraviolet Rays
• alpha-MSH (metabolism)
• beta Catenin (metabolism)
• p21-Activated Kinases (antagonists & inhibitors, metabolism, pharmacology)