title: 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.affiliation: Department of Biochemistry and Medical Research Center, College of Medicine, Chungbuk National University, Cheongju, Korea.
authors.forename: Cheong-Yong
authors.initials: CY
authors.lastname: Yun
authors.affiliation: Department of Biochemistry and Medical Research Center, College of Medicine, Chungbuk National University, Cheongju, Korea.
authors.forename: Soon-Tae
authors.initials: ST
authors.lastname: You
authors.affiliation: R&D Center, Hanbul Cosmetics Co. Ltd, Chungbuk, Korea. Electronic address: egkim@chungbuk.ac.kr.
authors.forename: Jin-Hwa
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Dermatology, Seoul National University, Seoul, Korea.
authors.forename: Jin H
authors.initials: JH
authors.lastname: Chung
authors.affiliation: College of Pharmacy and CBITRC, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Medical Research Center, College of Medicine, Chungbuk National University, Cheongju, Korea. Electronic address: eyshin@chungbuk.ac.kr.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Shin
authors.affiliation: Department of Biochemistry and Medical Research Center, College of Medicine, Chungbuk National University, Cheongju, Korea.
authors.forename: Eung-Gook
authors.initials: EG
authors.lastname: Kim
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D066298:In Vitro Techniques; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008812:Mice, Hairless; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D014466:Ultraviolet Rays; D000521:alpha-MSH / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; C550923:PF 3758309; D011720:Pyrazoles; D011758:Pyrroles; D051176:beta Catenin; D000521:alpha-MSH; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C492065:Pak4 protein, mouse; D054462:p21-Activated Kinases