title: Pyridinyl imidazole compounds interfere with melanosomes sorting through the inhibition of cyclin G-associated Kinase, a regulator of cathepsins maturation.
abstract: Transfer of melanin-containing melanosomes from melanocytes to neighboring keratinocytes results in skin pigmentation. Pharmacological modulation of melanosomal transfer has recently gained much attention as a strategy for modifying normal or abnormal pigmentation. In this study, while investigating the impact of pyridinyl imidazole (PI) compounds, a class of p38 MAPK inhibitors, on melanocyte differentiation we observed that some, but not all PIs interfere with the physiological melanosome sorting producing a strong retention of melanin in the intracellular compartment associated with a general reduction of melanin synthesis. Electron microscopy studies illustrated an accumulation of melanosomes inside melanocytes with enrichment in immature melanosome at stages II and III at the end of dendrites. We identified cyclin G-associated kinase GAK, a protein expressed ubiquitously in various tissues, as the off-target responsible of intracellular melanin accumulation and we report evidence that reduced GAK-dependent cathepsin maturation is implicated in melanosome sorting deficiency. The co-regulation of GAK and cathepsin B and L expression with the melanogenic biosynthetic pathway in normal human melanocytes as well as in B16-F0 melanoma cells strengthen the idea that these proteins represent new possible targets for prevention and treatment of irregular pigmentation.
authors.affiliation: Laboratory of Cutaneous Physiopathology, San Gallicano Dermatologic Institute, IRCCS, Rome 00144, Italy. Electronic address: bellei@ifo.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bellei
authors.affiliation: Laboratory of Cutaneous Physiopathology, San Gallicano Dermatologic Institute, IRCCS, Rome 00144, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Pitisci
authors.affiliation: Department of Plastic and Reconstructive Surgery, San Gallicano Dermatologic Institute, IRCCS, Rome 00144, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Migliano
authors.affiliation: Laboratory of Cutaneous Physiopathology, San Gallicano Dermatologic Institute, IRCCS, Rome 00144, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Cardinali
authors.affiliation: Laboratory of Cutaneous Physiopathology, San Gallicano Dermatologic Institute, IRCCS, Rome 00144, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Picardo
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020460:Melanosomes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012880:Skin Pigmentation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins; D011725:Pyridines; D034741:RNA, Small Interfering; C029899:imidazole; D014442:Monophenol Monooxygenase; C486325:GAK protein, human; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002403:Cathepsins; C023666:pyridine
keywords: Cathepsin; GAK; MAP Kinases; Melanosomes; Pigmentation; Pyridinyl imidazole compounds