{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q08874","secondaryAccessions":["A0A0N4SVJ5","O08885","O88203","Q08843","Q3U2D2","Q60781","Q60782","Q9JIJ0","Q9JIJ1","Q9JIJ2","Q9JIJ3","Q9JIJ4","Q9JIJ5","Q9JIJ6","Q9JKX9"],"uniProtkbId":"MITF_MOUSE","entryAudit":{"firstPublicDate":"2001-02-21","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2017-07-05","entryVersion":221,"sequenceVersion":4},"annotationScore":5.0,"organism":{"scientificName":"Mus musculus","commonName":"Mouse","taxonId":10090,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Glires","Rodentia","Myomorpha","Muroidea","Muridae","Murinae","Mus","Mus"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"Microphthalmia-associated transcription factor"}}},"genes":[{"geneName":{"value":"Mitf"},"synonyms":[{"value":"Bw"},{"value":"Mi"},{"value":"Vit"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O75030"}],"value":"Transcription factor that acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis (By similarity). Binds to M-boxes (5'-TCATGTG-3') and symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoter of pigmentation genes, such as tyrosinase (TYR) (By similarity). Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, MITF phosphorylation by MTOR promotes its inactivation (By similarity). Upon starvation or lysosomal stress, inhibition of MTOR induces MITF dephosphorylation, resulting in transcription factor activity (By similarity). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1) (By similarity). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O75030"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14975237"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23028343"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23207919"}],"value":"Homodimer or heterodimer; dimerization is mediated via the coiled coil region (PubMed:23207919). Efficient DNA binding requires dimerization with another bHLH protein (PubMed:23207919). Binds DNA in the form of homodimer or heterodimer with either TFE3, TFEB or TFEC (PubMed:23207919). Interacts with small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD); promoting its recruitment to lysosomal membrane in the presence of nutrients (By similarity). Interacts with KARS1 (PubMed:14975237). Identified in a complex with HINT1 and CTNNB1 (By similarity). Interacts with VSX2 (PubMed:23028343)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O75030"}],"value":"When nutrients are present, recruited to the lysosomal membrane via association with GDP-bound RagC/RRAGC (or RagD/RRAGD): it is then phosphorylated by MTOR. Phosphorylation by MTOR promotes ubiquitination and degradation. Conversely, inhibition of mTORC1, starvation and lysosomal disruption, promotes dephosphorylation and translocation to the nucleus. Phosphorylation by MARK3/cTAK1 promotes association with 14-3-3/YWHA adapters and retention in the cytosol"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8622664"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O75030"}],"value":"Cytoplasm","id":"SL-0086"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O75030"}],"value":"Lysosome membrane","id":"SL-0157"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"A"},"isoformIds":["Q08874-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"A1"},"isoformIds":["Q08874-2"],"sequenceIds":["VSP_002133"],"isoformSequenceStatus":"Described"},{"name":{"value":"A2"},"isoformIds":["Q08874-3"],"sequenceIds":["VSP_002131","VSP_002134","VSP_002136"],"isoformSequenceStatus":"Described"},{"name":{"value":"H"},"isoformIds":["Q08874-4"],"sequenceIds":["VSP_002129"],"isoformSequenceStatus":"Described"},{"name":{"value":"H1"},"isoformIds":["Q08874-5"],"sequenceIds":["VSP_002129","VSP_002132"],"isoformSequenceStatus":"Described"},{"name":{"value":"H2"},"isoformIds":["Q08874-6"],"sequenceIds":["VSP_002129","VSP_002132","VSP_002135"],"isoformSequenceStatus":"Described"},{"name":{"value":"H3"},"isoformIds":["Q08874-7"],"sequenceIds":["VSP_002129","VSP_002133"],"isoformSequenceStatus":"Described"},{"name":{"value":"M"},"isoformIds":["Q08874-8"],"sequenceIds":["VSP_002130"],"isoformSequenceStatus":"Described"},{"name":{"value":"M1"},"isoformIds":["Q08874-9"],"sequenceIds":["VSP_002130","VSP_002134"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8343963"}],"value":"In the adult, expressed at high levels in the heart, skin, skeletal muscle, intestine, stomach, kidney, ovary, lung, spleen and brain. In the embryo, expressed in developing eye, ear, skin and heart. Isoform M is expressed in melanocytes and also in the embryonic and adult heart while isoform A and isoform H are more widely expressed"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"23207919"}],"value":"The leucine zipper region is part of a larger coiled coil"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O75030"}],"value":"When nutrients are present, phosphorylation by MTOR at Ser-5 via non-canonical mTORC1 pathway promotes ubiquitination by the SCF(BTRC) complex, followed by degradation (By similarity). Phosphorylation at Ser-405 significantly enhances the ability to bind the tyrosinase promoter (By similarity). Phosphorylation by MARK3/cTAK1 at Ser-280 promotes association with 14-3-3/YWHA adapters and retention in the cytosol (By similarity). Phosphorylated at Ser-180 and Ser-516 following KIT signaling, triggering a short live activation: Phosphorylation at Ser-180 and Ser-516 by MAPK and RPS6KA1, respectively, activate the transcription factor activity but also promote ubiquitination and subsequent degradation by the proteasome (By similarity). Phosphorylated in response to blue light (415nm) (By similarity)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"O75030"}],"value":"Ubiquitinated by the SCF(BTRC) and SCF(FBXW11) complexes following phosphorylation ar Ser-5 by MTOR, leading to its degradation by the proteasome (By similarity). Ubiquitinated following phosphorylation at Ser-180, leading to subsequent degradation by the proteasome (By similarity). Deubiquitinated by USP13, preventing its degradation (By similarity)"}],"commentType":"PTM"},{"commentType":"DISEASE","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10400990"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7874168"}],"value":"Defects in Mitf are the cause of microphthalmia (mi), a condition characterized by loss of pigmentation; reduced eye size; failure of secondary bone resorption; reduced numbers of mast cells; early onset of deafness, and which gives rise to a number of different phenotypes. Among them, microphthalmia-eyeless white (mi-ew) has a normal appearance at the heterozygous state, but shows white coat; eyes almost absent and eyelids never open at homozygosity. Microphthalmia-black and white spot (mi-bws) is normal at heterozygosity, and presents white spots and black eyes at homozygous state. Microphthalmia-white (mi-wh) has reduced coat color and eye pigmentation; spots on toes, tail and belly; inner ear defects at heterozygosity, and at homozygosity shows white coat; eyes small and inner iris slightly pigmented; spinal ganglia, adrenal medulla and dermis smaller than normal, and inner ear defects. Microphthalmia-vitiligo (mi-vi) has normal phenotype at heterozygosity, but shows gradual depigmentation of coat, skin and eyes; and retinal degeneration at homozygosity. Microphthalmia-spotted (mi-sp) shows normal phenotype; at homozygosity, however, tyrosinase activity in skin is reduced. Microphthalmia-defective irism (mi-di) has reduced retinal pigmentation at heterozygosity and shows white coat; eyes of reduced sized and possible mild osteoporosis at homozygosity. Microphthalmia-cloudy eyed (mi-ce) has a normal appearance at the heterozygous state, but shows white coat; eyes of reduced size and unpigmented at homozygosity. Microphthalmia-red-eyed white (mi-rw) has a normal appearance at the homozygous state, but shows white coat with one or more pigmented spots around the head/and or tail; eyes are small and red at heterozygosity. Microphthalmia-black-eyed white (mi-bw) shows a white coat but normal sized eyes which reamin black at homozygosity"}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the MiT/TFE family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":526,"modifier":"EXACT"}},"description":"Microphthalmia-associated transcription 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