title: Signaling pathways in melanosome biogenesis and pathology.
abstract: Melanosomes are the specialized intracellular organelles of pigment cells devoted to the synthesis, storage and transport of melanin pigments, which are responsible for most visible pigmentation in mammals and other vertebrates. As a direct consequence, any genetic mutation resulting in alteration of melanosomal function, either because affecting pigment cell survival, migration and differentiation, or because interfering with melanosome biogenesis, transport and transfer to keratinocytes, is immediately translated into color variations of skin, fur, hair or eyes. Thus, over 100 genes and proteins have been identified as pigmentary determinants in mammals, providing us with a deep understanding of this biological system, which functions by using mechanisms and processes that have parallels in other tissues and organs. In particular, many genes implicated in melanosome biogenesis have been characterized, so that melanosomes represent an incredible source of information and a model for organelles belonging to the secretory pathway. Furthermore, the function of melanosomes can be associated with common physiological phenotypes, such as variation of pigmentation among individuals, and with rare pathological conditions, such as albinism, characterized by severe visual defects. Among the most relevant mechanisms operating in melanosome biogenesis are the signal transduction pathways mediated by two peculiar G protein-coupled receptors: the melanocortin-1 receptor (MC1R), involved in the fair skin/red hair phenotype and skin cancer; and OA1 (GPR143), whose loss-of-function results in X-linked ocular albinism. This review will focus on the most recent novelties regarding the functioning of these two receptors, by highlighting emerging signaling mechanisms and general implications for cell biology and pathology.
authors.affiliation: San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. schiaffino.mariavittoria@hsr.it
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Schiaffino
mesh_terms: D016117:Albinism, Ocular / Q000378:metabolism / Q000473:pathology; D000818:Animals; D005136:Eye Proteins / Q000378:metabolism; D006801:Humans; D020460:Melanosomes / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000378:metabolism; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D005136:Eye Proteins; C095276:GPR143 protein, human; D008562:Membrane Glycoproteins; D044102:Receptor, Melanocortin, Type 1
references.citation: Curr Biol. 2005 Mar 8;15(5):459-63
references.pmid: 15753041
references.citation: Cancer Res. 2005 May 15;65(10):4292-9
references.pmid: 15899821
references.citation: Pigment Cell Res. 2004 Apr;17(2):111-8
references.pmid: 15016299
references.citation: Nature. 2006 Sep 21;443(7109):340-4
references.pmid: 16988713
references.citation: Exp Eye Res. 2006 Feb;82(2):311-8
references.pmid: 16154128
references.citation: Pigment Cell Res. 2002 Apr;15(2):112-8
references.pmid: 11936268
references.citation: J Biol Chem. 2008 May 2;283(18):12564-70
references.pmid: 18292087
references.citation: Science. 2005 Dec 16;310(5755):1782-6
references.pmid: 16357253
references.citation: J Neurosci Res. 2007 Sep;85(12):2591-600
references.pmid: 17149749
references.citation: Annu Rev Genet. 2004;38:365-411
references.pmid: 15568981
references.citation: Nature. 1999 Mar 11;398(6723):148-52
references.pmid: 10086355
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):6025-30
references.pmid: 10811918
references.citation: J Proteome Res. 2003 Jan-Feb;2(1):69-79
references.pmid: 12643545
references.citation: Ann N Y Acad Sci. 2003 Jun;994:348-58
references.pmid: 12851335
references.citation: Pigment Cell Melanoma Res. 2010 Feb;23(1):27-40
references.pmid: 19995375
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9055-60
references.pmid: 8799153
references.citation: Nat Genet. 1995 May;10(1):13-9
references.pmid: 7647783
references.citation: Nat Rev Mol Cell Biol. 2007 Oct;8(10):786-97
references.pmid: 17878918
references.citation: Annu Rev Genet. 2003;37:67-90
references.pmid: 14616056
references.citation: Pigment Cell Res. 2006 Apr;19(2):104-11
references.pmid: 16524426
references.citation: J Cell Biol. 2001 Feb 19;152(4):809-24
references.pmid: 11266471
references.citation: Hum Mol Genet. 2008 Nov 15;17(22):3487-501
references.pmid: 18697795
references.citation: Int J Obes (Lond). 2008 Dec;32 Suppl 7:S19-27
references.pmid: 19136986
references.citation: J Cell Sci. 2006 May 15;119(Pt 10):2003-14
references.pmid: 16621890
references.citation: Ann N Y Acad Sci. 1963 Feb 15;100:497-533
references.pmid: 13992624
references.citation: Exp Eye Res. 2001 Mar;72(3):319-29
references.pmid: 11180981
references.citation: Genome Res. 1996 Sep;6(9):880-5
references.pmid: 8889556
references.citation: J Cell Biol. 2009 Oct 19;187(2):247-64
references.pmid: 19841138
references.citation: Pigment Cell Melanoma Res. 2009 Jun;22(3):251-2
references.pmid: 19302107
references.citation: J Neurochem. 2006 Feb;96(4):1201-11
references.pmid: 16445854
references.citation: Pigment Cell Res. 2001 Dec;14(6):485-90
references.pmid: 11775061
references.citation: FEBS Lett. 2009 Oct 6;583(19):3269-74
references.pmid: 19755124
references.citation: Pigment Cell Res. 2004 Aug;17(4):386-95
references.pmid: 15250941
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11336-41
references.pmid: 9736737
references.citation: Science. 1992 Aug 28;257(5074):1248-51
references.pmid: 1325670
references.citation: Nature. 1999 Mar 11;398(6723):152-6
references.pmid: 10086356
references.citation: J Biol Chem. 2009 Nov 13;284(46):31714-25
references.pmid: 19737927
references.citation: Am J Hum Genet. 2001 Nov;69(5):981-8
references.pmid: 11574907
references.citation: Hum Mol Genet. 2009 Dec 1;18(23):4530-45
references.pmid: 19717472
references.citation: J Cell Biol. 2002 Mar 4;156(5):855-65
references.pmid: 11864991
references.citation: Nat Genet. 1999 Sep;23(1):108-12
references.pmid: 10471510
references.citation: Hum Mol Genet. 2000 Dec 12;9(20):3011-8
references.pmid: 11115845
references.citation: Nature. 2007 Feb 22;445(7130):843-50
references.pmid: 17314970
references.citation: J Invest Dermatol. 2000 Oct;115(4):607-13
references.pmid: 10998131
references.citation: Pigment Cell Res. 2003 Aug;16(4):333-44
references.pmid: 12859616
references.citation: Science. 2007 Nov 30;318(5855):1418-23
references.pmid: 17947548
references.citation: Arch Ophthalmol. 1978 Sep;96(9):1621-5
references.pmid: 687204
references.citation: Nat Rev Mol Cell Biol. 2001 Oct;2(10):738-48
references.pmid: 11584301
references.citation: J Biol Chem. 2007 Sep 21;282(38):27557-61
references.pmid: 17635904
references.citation: Nature. 2007 Jul 5;448(7149):68-72
references.pmid: 17572665
references.citation: Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4358-64
references.pmid: 16303920
references.citation: Hum Mol Genet. 2000 Nov 22;9(19):2781-8
references.pmid: 11092754
references.citation: Pigment Cell Melanoma Res. 2008 Oct;21(5):509-16
references.pmid: 18821855
references.citation: FEBS Lett. 1996 Jun 24;389(1):61-5
references.pmid: 8682207
references.citation: Am J Hum Genet. 1998 Apr;62(4):800-9
references.pmid: 9529334
references.citation: J Cell Biol. 2003 May 12;161(3):521-33
references.pmid: 12732614
references.citation: Science. 1999 Oct 15;286(5439):525-8
references.pmid: 10521347
references.citation: Nat Rev Genet. 2003 Nov;4(11):876-88
references.pmid: 14634635
references.citation: J Clin Invest. 2002 Nov;110(10):1449-59
references.pmid: 12438443
references.citation: J Cell Sci. 2004 Jul 15;117(Pt 16):3659-68
references.pmid: 15252133
references.citation: Genes Dev. 2000 Jul 15;14(14):1712-28
references.pmid: 10898786
references.citation: Traffic. 2009 Feb;10(2):153-60
references.pmid: 18980611
references.citation: Arch Ophthalmol. 1976 Nov;94(11):1883-92
references.pmid: 985163
references.citation: Curr Biol. 2007 Dec 4;17(23):2030-4
references.pmid: 17997311
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1802-7
references.pmid: 19174519
references.citation: Exp Eye Res. 2007 Dec;85(6):806-16
references.pmid: 17920058
references.citation: J Invest Dermatol. 2006 Jan;126(1):172-81
references.pmid: 16417234
references.citation: Curr Opin Cell Biol. 2007 Aug;19(4):394-401
references.pmid: 17628466
references.citation: Hum Mol Genet. 2009 Apr 15;18(R1):R9-17
references.pmid: 19297406
references.citation: Nat Genet. 2001 Jan;27(1):40-7
references.pmid: 11137996
references.citation: J Biol Chem. 2005 Feb 18;280(7):5795-802
references.pmid: 15569680
references.citation: Invest Ophthalmol Vis Sci. 2008 Mar;49(3):868-72
references.pmid: 18326704
references.citation: Invest Ophthalmol Vis Sci. 2000 Dec;41(13):4333-7
references.pmid: 11095635
references.citation: Traffic. 2001 Mar;2(3):202-11
references.pmid: 11260525
references.citation: Pigment Cell Res. 2005 Dec;18(6):393-410
references.pmid: 16280005
references.citation: PLoS Biol. 2008 Sep 30;6(9):e236
references.pmid: 18828673
references.citation: Genomics. 1996 Oct 15;37(2):219-25
references.pmid: 8921399
references.citation: Mol Pharmacol. 2003 Dec;64(6):1271-6
references.pmid: 14645655
references.citation: Ann N Y Acad Sci. 1993 May 31;680:342-63
references.pmid: 8390157
references.citation: Science. 2007 Nov 30;318(5855):1453-5
references.pmid: 17962522
references.citation: Histopathology. 1980 May;4(3):243-54
references.pmid: 7390409
references.citation: Pigment Cell Res. 2005 Aug;18(4):227-33
references.pmid: 16029416
references.citation: Endocr Rev. 1980 Winter;1(1):1-27
references.pmid: 6262069
references.citation: Br J Dermatol. 2003 Sep;149(3):498-505
references.pmid: 14510981
references.citation: Cell. 2005 Dec 2;123(5):755-7
references.pmid: 16325568
references.citation: Pigment Cell Melanoma Res. 2009 Oct;22(5):623-34
references.pmid: 19493315
references.citation: PLoS Genet. 2008 Dec;4(12):e1000298
references.pmid: 19057677
references.citation: Nat Genet. 1995 Nov;11(3):328-30
references.pmid: 7581459
references.citation: Pigment Cell Melanoma Res. 2008 Feb;21(1):11-4
references.pmid: 18353139
references.citation: Endocr Rev. 2008 Aug;29(5):581-602
references.pmid: 18612139
references.citation: Mol Cell Biol. 2004 Aug;24(15):6550-9
references.pmid: 15254223
references.citation: FEBS Lett. 1992 Sep 14;309(3):417-20
references.pmid: 1516719
references.citation: J Comp Neurol. 2006 May 20;496(3):369-81
references.pmid: 16566005
references.citation: FASEB J. 2000 Jul;14(10):1265-78
references.pmid: 10877819
references.citation: Nat Cell Biol. 2008 Aug;10(8):912-22
references.pmid: 18641641
references.citation: Exp Cell Res. 2001 Aug 1;268(1):26-35
references.pmid: 11461115
references.citation: Pigment Cell Melanoma Res. 2009 Jun;22(3):253-4
references.pmid: 19323793
references.citation: J Comp Neurol. 1999 Mar 15;405(3):394-405
references.pmid: 10076934
references.citation: J Cell Biol. 1998 Dec 28;143(7):1899-918
references.pmid: 9864363
references.citation: Biochem Biophys Res Commun. 2005 Jan 14;326(2):349-54
references.pmid: 15582585
references.citation: Ann N Y Acad Sci. 2003 Jun;994:288-98
references.pmid: 12851328
references.citation: Mol Cell Endocrinol. 1993 May;93(1):C1-6
references.pmid: 8391494
references.citation: Pigment Cell Res. 2006 Apr;19(2):125-35
references.pmid: 16524428
references.citation: Hum Gene Ther. 2002 May 20;13(8):947-57
references.pmid: 12031127
references.citation: Invest Ophthalmol Vis Sci. 2008 Jul;49(7):3245-52
references.pmid: 18378571