# MITF

## Overview
MITF (Microphthalmia-associated transcription factor) is a gene that encodes for a transcription factor protein crucial for the development and function of melanocytes, cells responsible for pigment production in mammals. The MITF protein plays a pivotal role in the regulation of genes involved in melanin synthesis and is essential for melanocyte differentiation. Structurally, MITF is characterized by a basic helix-loop-helix-leucine zipper (bHLH-LZ) domain that facilitates DNA binding and dimerization, crucial for its function as a transcription factor (Vu2020User; Pogenberg2012Restricted). The protein's activity is regulated through various post-translational modifications, influencing its stability and interaction with other proteins (Goding2000Mitf). Mutations in the MITF gene can lead to pigmentary disorders and contribute to the pathogenesis of melanoma, underscoring its clinical significance in both genetic disorders and cancer (Levy2006MITF:; Cronin2009Frequent).

## Structure
The MITF protein, encoded by the MITF gene, exhibits a complex molecular structure characterized by multiple domains that contribute to its function as a transcription factor. The primary structure of MITF includes a basic helix-loop-helix-leucine zipper (bHLH-LZ) domain, which is essential for DNA binding and dimerization. This domain allows MITF to form homodimers or heterodimers within the MiT-TFE family of transcription factors, but not with other bHLH-Zip family proteins (Vu2020User; Pogenberg2012Restricted).

MITF also contains transactivation domains located at both the amino-terminal and carboxy-terminal regions, which interact with transcription adaptor proteins such as p300 and CBP (Goding2000Mitf). The protein's tertiary structure includes a unique three-residue insertion in the leucine zipper region, causing a significant kink in one of the zipper helices, which restricts its ability to heterodimerize with other bHLHZip proteins that lack this insertion (Pogenberg2012Restricted).

Post-translational modifications of MITF, such as phosphorylation, ubiquitination, and sumoylation, play significant roles in regulating the protein's function and stability. Specific phosphorylation sites include Ser73, Ser298, and Ser409, which are targeted by various kinases including GSK-3β, ERK2, and members of the p90 Rsk family (Goding2000Mitf; Hartman2014MITF).

MITF exists in several splice variant isoforms, which differ mainly at their N-termini, influenced by alternative splicing events. These isoforms include MITF-M, predominantly expressed in melanocytes, and others like MITF-A and MITF-H, which have distinct roles in different tissues (Shibahara2001Microphthalmia-Associated).

## Function
MITF (Microphthalmia-associated transcription factor) is a transcription factor that is essential for the development, function, and survival of melanocytes, the cells responsible for pigment production in the skin, hair, and eyes. It regulates the expression of various genes involved in melanocyte differentiation and melanin synthesis, including tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT), which are critical enzymes in the melanin production pathway (Levy2006MITF:). MITF binds to E-box sequences in the promoters of these genes, facilitating their transcription (Levy2006MITF:).

Beyond its role in pigmentation, MITF also influences other cellular processes such as cell cycle control, survival, and differentiation. It regulates genes like CDK2, which is essential for cell cycle progression, and BCL2, an anti-apoptotic factor, thereby playing a role in the clonogenic growth of melanoma cells and the survival of melanocytes (Levy2006MITF:). MITF's activity is modulated by various kinases and interacts with other transcription factors and proteins, such as SOX10 and LEF1, which are crucial for neural-crest development and signaling (Levy2006MITF:).

Additionally, MITF is involved in maintaining the normal function and homeostasis of melanocytes, which includes protecting against UV-induced skin cancers by regulating pigment biology (Levy2006MITF:). Mutations in MITF can lead to disorders like Waardenburg syndrome type IIA, characterized by pigmentary abnormalities and hearing loss, underscoring its importance in human health (Levy2006MITF:).

## Clinical Significance
MITF mutations are linked to several genetic disorders and cancers, notably impacting melanocyte function and development. In the context of genetic disorders, mutations in MITF are associated with Waardenburg Syndrome Type 2A (WS2A) and Tietz Syndrome (TS). WS2A is characterized by sensorineural hearing loss and pigmentation anomalies, while TS presents with profound congenital hearing loss and generalized hypopigmentation (Léger2012Novel; Grill2013MITF; Oliveira2021Expanding). These conditions underscore the critical role of MITF in melanocyte viability and the development of auditory and pigment cells.

In cancer biology, MITF is a pivotal factor in melanoma, a serious form of skin cancer. Mutations and amplifications of MITF contribute to melanomagenesis by altering its transcriptional activity, which can promote the proliferation of melanocytes (Cronin2009Frequent). The gene's role in melanoma is further complicated by its interaction with other genetic pathways, including mutations in the BRAF gene, which are often found concurrently in melanoma cases (Cronin2009Frequent).

Moreover, the MITF E318K variant has been identified as an intermediate-risk variant for melanoma, associated with a doubled risk of the disease in carriers. This variant is also linked to increased susceptibility to other cancers, including kidney cancer, highlighting the broader implications of MITF mutations beyond melanocyte-related conditions (Oliveira2021Expanding).

## Interactions
MITF interacts with a variety of proteins and nucleic acids, playing a crucial role in transcriptional regulation and melanoma progression. It forms complexes with p300/CBP, a histone acetyl transferase, which enhances MITF's transcriptional activity upon phosphorylation at Ser 73. However, this phosphorylation also promotes interaction with PIAS3, attenuating its transcriptional activity, a counteraction further modulated by phosphorylation at Ser 409 by p90 RSK (Hartman2014MITF). MITF also interacts with the BRM and BRG1 subunits of the SWI/SNF complex, influencing the activation of specific MITF-dependent genes (Hartman2014MITF).

In the context of melanoma, MITF interacts with RAF proteins, including ARAF, BRAF, and CRAF. This interaction, crucial for phenotype switching in melanoma cells, leads to the relocalization of MITF from the nucleus to the cytoplasm, impacting its transcriptional activity (Estrada2022MITF). Additionally, MITF collaborates with β-catenin, redirecting β-catenin's transcriptional activity from Wnt-regulated genes to MITF-specific target promoters, a process confirmed through chromatin immunoprecipitation assays (Schepsky2006The). These interactions underscore MITF's central role in the regulatory networks influencing melanocyte function and melanoma progression.


## References


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[2. (Oliveira2021Expanding) Leandro Jonata Carvalho Oliveira, Aline Bobato Lara Gongora, Fabiola Ambrosio Silveira Lima, Felipe Sales Nogueira Amorim Canedo, Carla Vanessa Quirino, Janina Pontes Pisani, Maria Isabel Achatz, and Benedito Mauro Rossi. Expanding the phenotype of e318k (c.952g > a) mitf germline mutation carriers: case series and review of the literature. Hereditary Cancer in Clinical Practice, July 2021. URL: http://dx.doi.org/10.1186/s13053-021-00189-8, doi:10.1186/s13053-021-00189-8. (4 citations) 10.1186/s13053-021-00189-8](https://doi.org/10.1186/s13053-021-00189-8)

[3. (Estrada2022MITF) Charlène Estrada, Liliana Mirabal-Ortega, Laurence Méry, Florent Dingli, Laetitia Besse, Cedric Messaoudi, Damarys Loew, Celio Pouponnot, Corine Bertolotto, Alain Eychène, and Sabine Druillennec. Mitf activity is regulated by a direct interaction with raf proteins in melanoma cells. Communications Biology, January 2022. URL: http://dx.doi.org/10.1038/s42003-022-03049-w, doi:10.1038/s42003-022-03049-w. (10 citations) 10.1038/s42003-022-03049-w](https://doi.org/10.1038/s42003-022-03049-w)

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[6. (Levy2006MITF:) Carmit Levy, Mehdi Khaled, and David E. Fisher. Mitf: master regulator of melanocyte development and melanoma oncogene. Trends in Molecular Medicine, 12(9):406–414, September 2006. URL: http://dx.doi.org/10.1016/j.molmed.2006.07.008, doi:10.1016/j.molmed.2006.07.008. (1380 citations) 10.1016/j.molmed.2006.07.008](https://doi.org/10.1016/j.molmed.2006.07.008)

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[11. (Grill2013MITF) Christine Grill, Kristín Bergsteinsdóttir, Margrét H. Ögmundsdóttir, Vivian Pogenberg, Alexander Schepsky, Matthias Wilmanns, Veronique Pingault, and Eiríkur Steingrímsson. Mitf mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. Human Molecular Genetics, 22(21):4357–4367, June 2013. URL: http://dx.doi.org/10.1093/hmg/ddt285, doi:10.1093/hmg/ddt285. (77 citations) 10.1093/hmg/ddt285](https://doi.org/10.1093/hmg/ddt285)

[12. (Pogenberg2012Restricted) Vivian Pogenberg, Margrét H Ögmundsdóttir, Kristín Bergsteinsdóttir, Alexander Schepsky, Bengt Phung, Viktor Deineko, Morlin Milewski, Eiríkur Steingrímsson, and Matthias Wilmanns. Restricted leucine zipper dimerization and specificity of dna recognition of the melanocyte master regulator mitf. Genes & Development, 26(23):2647–2658, December 2012. URL: http://dx.doi.org/10.1101/gad.198192.112, doi:10.1101/gad.198192.112. (162 citations) 10.1101/gad.198192.112](https://doi.org/10.1101/gad.198192.112)