MITF

The leucine zipper region is part of a larger coiled coil.

Transcription factor that acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis (PubMed:10587587, PubMed:22647378, PubMed:27889061, PubMed:9647758). 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) (PubMed:10587587, PubMed:22647378, PubMed:27889061, PubMed:9647758). 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 (PubMed:36608670). Upon starvation or lysosomal stress, inhibition of MTOR induces MITF dephosphorylation, resulting in transcription factor activity (PubMed:36608670). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1) (PubMed:10587587, PubMed:22647378, PubMed:27889061, PubMed:9647758). 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 (PubMed:10587587, PubMed:22647378, PubMed:27889061, PubMed:9647758).

Waardenburg syndrome 2A

WS2A

WS2 is a genetically heterogeneous, autosomal dominant disorder characterized by sensorineural deafness, pigmentary disturbances, and absence of dystopia canthorum. The frequency of deafness is higher in WS2 than in WS1.

None

The disease is caused by variants affecting the gene represented in this entry.

Tietz albinism-deafness syndrome

TADS

An autosomal dominant disorder characterized by generalized hypopigmentation and congenital, bilateral, profound sensorineural deafness.

None

The disease is caused by variants affecting the gene represented in this entry.

Melanoma, cutaneous malignant 8

CMM8

A malignant neoplasm of melanocytes, arising de novo or from a pre-existing benign nevus, which occurs most often in the skin but may also involve other sites.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness

COMMAD

An autosomal recessive syndrome characterized by severe microphthalmia, profound congenital sensorineural hearing loss, lack of pigment in the hair, skin, and eyes, macrocephaly, facial dysmorphism, and osteopetrosis.

None

The disease is caused by variants affecting the gene represented in this entry. An allelic combination involving at least one dominant-negative mutation, inherited in a recessive manner, represents the underlying molecular mechanism leading to COMMAD syndrome.

Variations affecting this gene are associated with susceptibility to pheochromocytomas and paragangliomas, rare neural crest-derived tumors with an approximate incidence of 1:300,000/year.

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 (PubMed:36608670). Phosphorylation at Ser-405 significantly enhances the ability to bind the tyrosinase promoter (PubMed:10587587). Phosphorylation by MARK3/cTAK1 at Ser-280 promotes association with 14-3-3/YWHA adapters and retention in the cytosol (PubMed:16822840). 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 (PubMed:10673502). Phosphorylated in response to blue light (415nm) (PubMed:28842328).

Ubiquitinated by the SCF(BTRC) and SCF(FBXW11) complexes following phosphorylation ar Ser-5 by MTOR, leading to its degradation by the proteasome (PubMed:36608670). Ubiquitinated following phosphorylation at Ser-180, leading to subsequent degradation by the proteasome (PubMed:10673502). Deubiquitinated by USP13, preventing its degradation (PubMed:10673502).

Belongs to the MiT/TFE family.

Expressed in melanocytes (at protein level).

Isoform A2

Expressed in the retinal pigment epithelium, brain, and placenta (PubMed:9647758). Expressed in the kidney (PubMed:10578055, PubMed:9647758).

Isoform C2

Expressed in the kidney and retinal pigment epithelium.

Isoform H1

Expressed in the kidney.

Isoform H2

Expressed in the kidney.

Isoform M1

Expressed in melanocytes.

Isoform Mdel

Expressed in melanocytes.

• Nucleus
• Cytoplasm
• Lysosome membrane
• 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 (PubMed:23401004, PubMed:36608670). Phosphorylation by MTOR promotes ubiquitination and degradation (PubMed:36608670). Conversely, inhibition of mTORC1, starvation and lysosomal disruption, promotes dephosphorylation and translocation to the nucleus (PubMed:36608670). Phosphorylation by MARK3/cTAK1 promotes association with 14-3-3/YWHA adapters and retention in the cytosol (PubMed:16822840).

BHLHE32, MITF, Microphthalmia-associated transcription factor, Class E basic helix-loop-helix protein 32, bHLHe32

• entrezGene:4286
• omim:156845
• swissprot:O75030

Proteins

Epigenetics

• Oncology

58795Da