Search results for MITF

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Reaction (30 results from a total of 95)

Identifier: R-HSA-9857375
Species: Homo sapiens
Compartment: nucleoplasm
Based on electrophoretic mobility shift assays conducted with mouse proteins, MITF dimerizes with itself or any of the related MiT family member transcription factors TFE3, TFEB and TFEC (Hemesath et al, 1994; Fisher et al, 1991; Zhao et al, 1993), but not with other BHLH or BHLH-Zip transcription factors. Dimerization appears to be required for DNA binding, and there is some evidence that in the absence of DNA, the transcription factors may form tetrameric complexes (Fisher et al, 1991). DNA is contacted in the major groove by the basic domain of MITF (Hemesath et al, 1994; Pogenberg et al, 2012; reviewed by Goding and Arnheiter, 2019).
TFEC shows more restricted expression than other members of the MiT family, while TFEB, TFE3 and MITF are widely expressed (Hemesath et al, 1994; Rehli et al 199; Kuiper et al, 2004). Despite the ability of each of their encoded proteins to form heterodimers with MITF, knockouts of TFE3, TFEB and TFEC do not affect melanocyte development, suggesting that only MITF homodimers are essential for this role (Steingrimsson et al, 2002; reviewed in Hou and Pavan, 2008; Goding and Arnheiter, 2019)
Identifier: R-HSA-9730412
Species: Homo sapiens
Compartment: nucleoplasm
MITF (microphthalmia-associated transcription factor) is a key regulator of melanocyte biology. Melanocytes are specialized cells that contain melanosomes, organelles required for the synthesis of melanin (reviewed in Goding and Arnheiter, 2019). MITF is a critical determiner of melanocyte cell fate and controls expression of many of the genes involved in melanin biosynthesis, such as TYR, TYRP1 and DCT, as well as genes involved in cell adhesion and intracellular trafficking (which is required for melanosome transport, among other things) (Cheli et al, 2010; Ullrich et al, 1995; Chiaverini et al, 2008; Alves et al, 2017; reviewed in Goding and Arnheiter, 2019; Mort et al, 2015; White and Zon, 2008).
MITF expression is itself tightly regulated in a cell- and developmental stage specific manner. Melanocytes are derived from a multipotent precursor in the neural crest that can assume both a Schwann cell/glial cell fate and a melanocyte fate (reviewed in Mort et al, 2015; White and Zon, 2008). Cells destined to become melanocytes arise from neural crest cells along the entire vertebrate axis and migrate in the trunk region dorsolaterally from the neural crest through the dermis during development. Melanocytes can also arise from glial/Schwann cell precursors that migrate earlier in a ventral pattern. MITF expression is repressed in the multipotent precursor by a number of factors including SOX2, SOX9 and FOXD3 (Thomas and Erickson, 2009; Nitzan et al, 2013 a,b; Adameyko et al, 2012) and upregulated as cells undergo melanocyte fate determination through the action of transcription factors such as PAX3 and SOX10 (Bondurand et al, 2000; Potterf et al, 2000; reviewed in Goding and Arnheiter, 2019; Mort et al, 2015).
Identifier: R-HSA-9732125
Species: Homo sapiens
Compartment: nucleoplasm
SOX2 is a transcriptional repressor that is present on the promoter of the MITF gene in neural crest cells prior to melanocyte fate specification. With FOXD3, SOX2 represses MITF expression and promotes instead the development of the Schwann cell precursor fate (Adameyko et al, 2012). Although the mechanisms for lifting SOX2-mediated repression in the melanocyte cell line are not known, once expressed, MITF itself represses further SOX2 expression (Adameyko et al, 2012; reviewed in Mort et al, 2015; Goding and Arnheiter, 2019).
Identifier: R-HSA-3232162
Species: Homo sapiens
Compartment: nucleoplasm
PIAS3 SUMOylates MITF with SUMO1 at lysine-289 and lysine-423 (lysine-182 and lysine-316 of the M2 isoform, Miller et al. 2005). SUMOylation reduces transcriptional activation by MITF at promoters containing multiple binding sites for MITF.
Identifier: R-HSA-9858286
Species: Homo sapiens
Compartment: nucleoplasm
POU3F2, also known as BRN2, is a transcription factor that has roles in neuronal development and plays roles in the development of the melanocyte lineage and in the progression of melanoma downstream of the WNT, MAPK and PI3K pathways (Goodall et al, 2004a; Goodall et al, 2004b; Bonvin et al, 2012; reviewed in Fane et al, 2019; Goding and Arnheiter, 2019; Cook et al, 2008). POU3F2 has been shown to bind directly to promoter elements upstream of the MITF gene by EMSA (Herbert et al, 2019; Goodall et al, 2008). In melanoma cells, POU3F2 has been reported as both an activator and a repressor of MITF expression (Wellbrock et al, 2008; Goodall et al, 2008). The ability of POU3F2 to bind DNA may depend in part on a conformational change in the N-terminal region in response to p38-dependent phosphorylation at residues S91 and S96, providing a link through p38 to the UV stress response (Herbert et al, 2019).
The relationship of POU3F2 and MITF expression appears to be somewhat context dependent. During melanogenesis, POU3F2 is expressed in neural crest precursor cells in a manner that depends on WNT, PI3K and MAPK signaling, but is not expressed in melanoblasts or in melanocytes that express MITF (Goodall et al, 2004a, Cook et al, 2003). During melanoma progression, POU3F2 and MITF are expressed in distinct subsets of cells within a tumor (Goodall et al, 2008, Thurber et al, 2011), possibly as the result of a negative feedback loop established through the MITF target miR-211 that downregulates POU3F2 levels (Boyle et al, 2011). POU3F2 expression has a role in driving invasion of melanoma cells, and the relative levels of MITF and POU3F2 may act to regulate the proliferative versus invasive properties of these cells (reviewed in Fane et al, 2019; Goding and Arnheiter et al, 2019).
In addition to its role at the promoter of the MITF gene, POU3F2 has also been implicated in the DNA damage response (DDR) pathway in melanoma cells by virtue of its interaction with DDR factors such as DNA-dependent protein kinases DNAPK and PRKDC, PARP1 and the Ku70/Ku80 dimer (Herbert et al, 2019). The interaction of POU3F2 and Ku70/80 dimer promotes resolution of DNA damage through the mutation prone non-homologous end-joining (NHEJ) pathway rather than through homologous recombination. In this way, POU3F2 may contribute to the high mutation burden of melanoma cell lines (Herbert et al, 2019; reviewed in Goding and Arnheiter, 2019; Fane et al, 2019).

Identifier: R-HSA-9858238
Species: Homo sapiens
Compartment: nucleoplasm
Based on studies in African striped mouse, house mouse and chipmunk, ALX3 binds to conserved elements in the MITF promoter to repress transcription (Mallarino et al, 2016). ALX3 (aristaless-like homeobox 3) is a homeodomain protein that is expressed in neural crest derived mesenchyme and acts as a transcriptional regulator (ten Berge 1998; Perez-Villamil et al, 2004). Human and mouse ALX3 share ~90% identity and the three identified binding sites in the MITF promoter are conserved (Mallarino et al, 2016). Although in some cases ALX3 has been shown to bind DNA as a dimer, dimerization does not appear to be absolutely required and the DNA binding properties of ALX3 are impacted by interaction with other nuclear proteins and by the particular cellular environment (Perez-Villamil et al, 2004). The precise role of ALX3 in the regulation of melanocyte development and melanoma progression are not yet known.
Identifier: R-HSA-9824653
Species: Homo sapiens
Compartment: nucleoplasm
Alpha-melanocyte-stimulating hormone (alpha MSH) stimulates transcription of MITF in developing melanocytes and in melanoma cells by promoting the cAMP-dependent phosphorylation of CREB1. Phosphorylated CREB1 binds to a CRE element in the MITF-M promoter as assessed by electrophoretic mobility shift assay and stimulates transcription of MITF (Bertolotto et al,1998; Price et al, 1998). CREB-stimulated transcriptional activation of the MITF-M promoter is also dependent on the upstream SOX10 binding site (Huber et al, 2003).
Identifier: R-HSA-9730407
Species: Homo sapiens
Compartment: nucleoplasm
SOX10 and PAX3 bind directly to cognate elements in the proximal MITF-M promoter to synergistically stimulate its transcription (Zhang et al, 2012; Potterf et al, 2000; Bondurand et al, 2000; Watanabe et al, 1998; reviewed in Mort, 2015; White and Ton, 2008; Goding and Arnheiter, 2019).
PAX3 is a DNA-binding transcription factor with roles in neural development and myogenesis that is expressed in the neural tube prior to neural crest migration (reviewed in Monsoro-Burq, 2015). PAX3 contains a homeobox domain and a paired domain that bind to consensus sequences ATTAAT and GGAAC, respectively (Chalepakis et al, 1994a,b). Consensus binding sites for PAX3 containing these elements have been identified in the promoter of the MITF gene (Watanabe et al, 1998; reviewed in Goding and Arnheiter, 2019).
SOX10 is a member of the sex-determining factor (SRY)-like, high mobility group family of transcription factors that are involved in cell lineage pathways (Schock and LaBonne, 2020). SOX10 is expressed in early migrating neural crest cells, some of which go on to develop into melanoblasts and melanocytes (Herbarth et al 1998; Pusch et al 1998; reviewed in Mort et al, 2015; White and Zon, 2008). SOX10 binding sites have been identified in the proximal and distal regions of the MITF promoter. These sites stimulate expression of reporter genes in vitro, are bound by SOX10 as assessed by electrophoretic mobility shift assays, and drive in vivo expression in mice (Bondurand et al, 2000; Potterf et al, 2000; Zhang et al, 2012; reviewed in Goding and Arnheiter, 2019).
SOX10 transcription factor activity is regulated by SUMOylation, and SOX10 has been shown to be sumoylated at lysine 55 in a UBE2I (also known as UBC9)-dependent manner (Girard et al, 2006; Taylor and La Bonne, 2005; Han et al, 2018). MAPK1-dependent phosphorylation of SOX10 at residues T240 and T244 interferes with the interaction of SOX10 with UBE2I and inhibits SOX10 transcription factor activity at the MITF promoter (Han et al, 2018). A direct transcriptional activation role for SOX10 K55 sumoylation at the MITF promoter has not been shown, however.
Identifier: R-HSA-9824598
Species: Homo sapiens
Compartment: nucleoplasm
Expression of the melanocyte-specific isoform of MITF is stimulated by WNT3A and WNT1 during melanocyte lineage development (Takeda et al, 2000). In response to WNT3A, LEF1 and CTNNB1 (beta catenin) bind to 3 LEF1 elements in the M-promoter of MITF to drive expression, as assessed by EMSA, ChIP and reporter gene assays. Mutation of the LEF1 binding site abolishes both the interaction of LEF1 with the promoter and the activation of MITF-M expression (Takeda et al, 2000; Dorsky et al, 2000; Widlund et al, 2002).
MITF protein has been shown to interact with LEF1 by co-immunoprecipitation, and MITF-M stimulates its own expression in a manner that is independent of its DNA binding (Saito et al, 2002, Wang et al 2018). MITF-responsive transcription is dose-dependent, with MITF-M synergizing with LEF1 at lower concentrations to stimulate its own transcription, but inhibiting expression at higher doses.
WNT-, beta-catenin- and LEF1-driven MITF expression is also seen in melanoma cell lines, where MITF contributes to proliferation and survival (Widlund et al, 2002).
Identifier: R-HSA-9825751
Species: Homo sapiens
Compartment: nucleoplasm
Deacetylation of HINT1 by SIRT promotes the interaction of MITF and HINT1, consequently restricting the transcription factor activity of MITF (Lee et al, 2004; Razin et al, 1999; Weiske et al, 2005; Genovese et al, 2009; Choudhary et al, 2009; Motzik et al, 2017; Jung et al, 2020).
Identifier: R-HSA-9858924
Species: Homo sapiens
Compartment: cytosol, nucleoplasm
MITF has been implicated in the regulation of expression of many components of the v-ATPase, including the cytosolic component ATP6V1G1 (Zhang et al, 2015). The v-ATPase is responsible for acidification of organelles such as the lysosome and the endosome. The lysosome is also a site of regulation of TORC1 (target of rapamycin complex 1) that promotes global protein synthesis. MITF-family members and TORC1 play varied but interconnected roles in the sensing and response to nutrient levels, with MITF either positively or negatively regulating TORC activity depending on context (reviewed in Martina et al, 2014), and TORC1 and RAG GTPases have been shown to regulate the localization of some MITF family members (Martina and Puertollano, 2019). MITF has also been implicated as a regulator in a subset of genes associated with autophagy and lysosome biogenesis (Ploper et al, 2015; Moller et al, 2019; reviewed in Ploper and Robertis, 2015; Goding and Arnheiter, 2019).
Identifier: R-HSA-9824587
Species: Homo sapiens
Compartment: nuclear envelope, mitochondrial outer membrane
MITF binds to the promoter of the BCL2 gene to upregulate its expression (McGill et al, 2002; Genovese et al, 2012). MITF-dependent regulation of the anti-apoptotic factor BCL2 contributes to the survival of the melanocyte lineage and to the progression of melanoma, as demonstrated by the loss of the melanocyte lineage in BCL2 knockout mice and in cell lines (Yamamura et al, 1996; Trisciuoglio et al, 2005; reviewed in Hou and Pavan, 2008; Cheli et al, 2010; Goding and Arnheiter, 2019; Soengas and Lowe, 2003). Overexpression of BCL2 decreases expression of the MITF target miR-211, decreases the proportion of nuclear MITF and reduces MITF occupancy on promoters of target genes such as GPR143 (also known as MLANA) and TRPM1 (De Luca et al, 2016).
Identifier: R-HSA-9858566
Species: Homo sapiens
Compartment: nucleoplasm, cytosol
CDK2 is expressed in the melanocyte lineage and in melanoma cells in a manner that depends on MITF binding to E-box elements in its promoter (Du et al, 2004). CDK2 and MITF are coordinately expressed in many melanoma cell lines and CDK2 expression may contribute to the pro-proliferative effect of MITF (Du et al, 2004; Azimi et al, 2018; reviewed in Goding and Arnheiter, 2019).
Identifier: R-HSA-9825837
Species: Homo sapiens
Compartment: nucleoplasm
MITF-dependent expression of CDKN1A is associated with cell cycle arrest and initiation of the MITF-dependent differentiation and pigmentation process (Carreira et al, 2005; Carreira et al, 2006; reviewed in Cheli et al, 2010; Goding and Arnheiter, 2019). In mouse embryonic fibroblasts, NIH3T3 cells and RAT1 cells, overexpression of MITF results in CDKN1A-dependent cell cycle arrest (Carreira et al, 2005). Despite this, the precise role of CDKN1A during development of the melanocyte lineage is unclear, as CDKN1A-deficient mice show no loss of pigmentation, while MITF in conjunction with BCL2 is essential for melanoblast survival (Deng et al, 1995; Hornyak et al, 2003; McGill et al, 2002; Hodgkinson et al, 1993; reviewed in Goding and Arnheiter, 2019; White and Zon, 2015)
Identifier: R-HSA-9858734
Species: Homo sapiens
Compartment: nucleoplasm
TERT encodes the telomerase responsible for maintenance of chromosome ends. TERT has been identified as a direct MITF target in melanoma cells by ChIP. Consistent with this, depletion of MITF causes a decrease in TERT mRNA by RNA seq and RT-qPCR (Strub et al, 2011). TERT is one of a number of potential MITF-dependent target genes involved in processes of DNA replication and damage repair (Strub et al, 2011; reviewed in Goding and Arnheiter, 2019)
Identifier: R-HSA-9856061
Species: Homo sapiens
Compartment: nucleoplasm, plasma membrane
CEACAM1 is a cell adhesion molecule that contributes to melanoma by influencing invasion and metastasis (reviewed in Goding and Arnheiter, 2019; Turcu et al 2016; Smart et al, 2021). CEACAM1 is a direct target of MITF-M as assessed by ChIP (Ullrich et al, 2015; Strub et al, 2011).
Identifier: R-HSA-9858297
Species: Homo sapiens
Compartment: nucleoplasm, plasma membrane
TRPM1 encodes a cation channel that allows passages of various cations from the extracellular space into the cytoplasm (reviewed in Marini et al, 2023; Chubanov et al, 2023). TRPM1 has been identified as a direct target of MITF-M in melanocytes, retinal pigment epithelial cells and melanoma cells (Hunter et al, 1998; Miller et al, 2004; Miller et al, 2005; Strub et al, 2011). Expression is frequently downregulated during melanoma progression (Duncan et al, 1998; Duncan et al, 2001). The significance of TRPM1 downregulation in melanoma is unclear. Intron 6 of TRPM1 contains the MIR211 gene encoding microRNA miR-211 which is therefore similarly downregulated in melanoma. Targets of miR-211 include the MITF promoter binding protein POU3F2 (also known as BRN2), AP1S2, IGFBP5, SOX11 and SERINC3). How the changes in levels of TRPM1, miR-211 and miR-211 targets contribute to melanoma progression remains to be clarified (Margue et al, 2013; Levy et al, 2010; Boyle et al, 2011; De Luca et al, 2016; reviewed in Goding and Arnheiter, 2019).
Identifier: R-HSA-9857585
Species: Homo sapiens
Compartment: nucleoplasm, cytoplasm
Through its direct binding and activation of DIAPH1 gene expression, MITF-M affects processes of proliferation and invasiveness in melanoma and normal melanocyte cells (Carreira et al, 2006; reviewed in Hou and Pavan, 2008; Goding and Arnheiter, 2019).
DIAPH1 is a formin protein that affects the actin cytoskeleton at least in part through RAC (Tsuji et al, 2002). Depletion of MITF in melanoma cells results in decreased expression of DIAPH1 and an aberrant F-actin organization including a rounded cell morphology that is rescued by expression of DIAPH1 (Carreira et al, 2006). High DIAPH1 levels are associated with high levels of the F-box protein SKP2, which promotes the degradation of the cell cycle inhibitor CDKN1B (p27kip1), thus stimulating cellular proliferation (Carrano et al, 1999; Tsvetkov et al, 1999; Mammoto et al, 2004). Consistent with this, depletion of MITF in melanoma cells is associated with a CDKN1B (p27kip1)-dependent cell cycle arrest (Carreira et al, 2006).
Identifier: R-HSA-9857590
Species: Homo sapiens
Compartment: nucleoplasm, cytoplasm
GMPR encodes guanosine monophosphate reductase, a tetrameric enzyme that catalyzes the deamination of GMP to inosine monophosphate (IMP). IMP can be converted into AMP or, through the action of inosine monophosphate dehydrogenase enzymes, can be converted back to GMP. In this way, IMP is a branch point in purine biosynthesis pathways (reviewed in D'Angiolella et al, 2014).
Expression of GMPR is decreased in a number of melanoma cell lines, resulting in dysregulation of GMP and AMP levels. These cells show elevated levels of GTP relative to normal cells (Wawrzyniak et al, 2013; Bianchi-Smirglia et al, 2017; reviewed in D'Angiolella et al, 2014). MITF expression is also decreased in melanoma cells and low MITF levels are correlated with increased invasive potential (Carreira et al, 2006; Giuliano et al, 2010; reviewed in Vachtenheim and Ondrusova, 2015).
GMPR is a direct target of MITF-M in melanoma and normal human melanocytes (Bianchi-Smiraglia et al, 2017; Strub et al, 2011; Hoek et al, 2008). Abrogation of MITF-M dependent GMPR expression results in elevated GTP levels, and increase in the formation of active, GTP-bound RAC1, RHOA and RHOC complexes, increased formation of invadopodia and increased invasive potential (Bianchi-Smiraglia et al, 2017; reviewed in D'Angiolella et al, 2014; Goding and Arnheiter, 2019).
Identifier: R-HSA-9859104
Species: Homo sapiens
Compartment: nucleoplasm, lysosomal lumen
ASAH1 is a ceramidase that cleaves ceramides into sphingosine and free fatty acids. ASAH1 expression is high in melanocytes and melanoma cells and has been implicated in regulation of MITF-M-dependent cellular proliferation (LeClerc et al, 2019; Realini et al, 2016; reviewed in Goding and Arnheiter, 2019). Ectopic expression of ASAH1 rescues the proliferation defect of MITF-depleted melanoma cells, while depletion of ASAH1 decreases cellular proliferation rates and increases cell invasiveness, consistent with the phenotypes seen with MITF (LeClerc et al, 2019).
Identifier: R-HSA-9858729
Species: Homo sapiens
Compartment: nucleoplasm
LIG1 encodes a DNA ligase involved in ligation of Okazaki fragments during DNA replication and repairing nicks in double-stranded DNA during DNA repair (Maffucci et al, 2018; reviewed in Howes and Tomkinson, 2012; Tomkinson et al, 2020). LIG1 was identified by ChIP as a direct MITF target in melanoma cells (Strub et al, 2011; reviewed in Goding and Arnheiter, 2019).
Identifier: R-HSA-9856462
Species: Homo sapiens
Compartment: nucleoplasm, cytosol
MYO5A is an actin-based motor protein that contributes to pigmentation by regulating the localization of melanosomes. In conjunction with complex members RAB27A and MLPH, MYO5A directs melanosomes to the periphery of melanocytes as a preliminary step to the transfers of melanosomes to adjacent keratinocytes (Bahadoran et al, 2001; Nagashima et al, 2002; Fukuda et al, 2002; Kuroda and Fukuda, 2004; reviewed in Seabra and Coudrier, 2004; Hume and Seabra, 2011).
MYO5A, like its co-complex member RAB27A, is a direct transcriptional target of MITF-M as assessed by ChIP and reporter gene assay (Strub et al, 2011; Alves et al, 2017; reviewed in Cheli et al, 2010; Goding and Arnheiter, 2019).
Identifier: R-HSA-9856460
Species: Homo sapiens
Compartment: nucleoplasm, melanosome membrane
RAB27A is a small GTPase with roles in melanosome localization. In its active, GTP-bound form it interacts with MYO5A and MLPH (also known as melanophilin) and the tripartite complex directs melanosomes to the ends of dendrites by virtue of the MYO5A:actin interaction. Cell peripheral localization facilitates the transfer of melanosomes out of the melanocytes into adjacent keratinocytes (Chiaverini et al, 2008; Alves et al, 2017; Bahadoran et al, 2001; Fukuda et al, 2002; Nagashima et al, 2002; Kuroda and Fukuda, 2004; reviewed in Seabra and Coudrier, 2004; Hume and Seabra, 2011).
RAB27A and MYO5A are both direct targets of MITF-M as assessed by ChIP, EMSA and reporter gene assay (Chiaverini et al, 2008; Strub et al, 2011; Alves et al, 2017; reviewed in Cheli et al, 2010; Goding and Arnheiter, 2019).
Identifier: R-HSA-9824979
Species: Homo sapiens
Compartment: nucleoplasm
GSK3B-dependent phosphorylation of MITF-M at residue S69 promotes its interaction with the nuclear export factor XPO1, also known as CRM1 (Ngeow et al, 2018). Nuclear export of MITF-M is dependent on the nuclear export sequence MxMLxM located at residues 74-80. Mutation of this site abrogates nuclear export of an MITF-M reporter in response to MAPK activation by TPA (12-O-tetradecanoylphorbol-13 acetate), supporting a model where sequential phosphorylations by MAPK1 and GSK3B at MITF-M serine residues S73 and S69 promote XPO1-dependent relocation of MITF-M to the cytosol (Ngeow et al, 2018; reviewed in Goding and Arnheiter, 2019).
Identifier: R-HSA-9856053
Species: Homo sapiens
Compartment: melanosome membrane, nucleoplasm
GPR143 encodes a GPCR that, with MLANA, plays a role in the maturation and localization of PMEL. In this capacity, GPR143 contributes to the melanosome maturation and organization (Cortese et al, 2005; Schaiffino and Tacchetti, 2005; Vetrini et al, 2004; Palmisano et al, 2008; Giordano et al, 2009; reviewed in Cheli et al, 2010). Regulation of GPR143 is controlled in part by the binding of MITF-M to an E-box element in the proximal promoter (Vetrini et al, 2004; Strub et al, 2011).
Identifier: R-HSA-9858636
Species: Homo sapiens
Compartment: nucleoplasm, cytosol
PLK1 has been identified as a direct target of MITF activation in melanoma cells by ChIP. Consistent with this, siRNA-mediated depletion of MITF causes a reduction in PLK1 protein and a concomitant increase in cells displaying mitotic aberrations in spindle and chromosome organization (Strub et al, 2011).
Identifier: R-HSA-9824994
Species: Homo sapiens
Compartment: nucleoplasm
MITF-M is phosphorylated by RPS6KA1 (also known as RSK1) at serine S409 downstream of activated SCF-KIT signaling during development (Wu et al, 2000). S409 phosphorylation primes MITF-M for subsequent phosphorylation by GSK3B at serine residues S397, S401 and S405 in the C-terminus, modifications that are associated with degradation of the protein (Ploper et al, 2015, reviewed in Goding and Arnheiter, 2019).
The relationship between MITF and KITLG-KIT during melanocyte differentiation is not totally clear. Mutations of KIT or its ligand are associated with pigmentation defects and depleted levels of mature melanocytes. KIT signaling appears to contribute to the migration and survival of melanoblasts during development (Wehrle-Haller and Weston, 1995; Wehrle-Haller et al, 2001; Tabone-Eglinger et al, 2012; Kunisada et al, 1998; reviewed in White and Zon, 2008). MITF-M and KIT also appear to reciprocally affect each other's expression: although KIT does not appear to be required for the initial expression of MITF during development, activated KIT signaling increases the transcription factor activity of MITF to a variable extent at different MITF-M target genes (Hou et al, 2000; Price et al, 1998, Wu et al, 2000, Hemesath et al, 1998). Similarly, expression of MITF-M has been shown to increase expression of KIT in some systems (Tsujimura et al, 1996; Opdecamp et al, 1997; reviewed in Hou and Pavan, 2008)
Identifier: R-HSA-9824977
Species: Homo sapiens
Compartment: nucleoplasm
MITF-M is phosphorylated by MAPK1 (also known as ERK2) in response to signaling through KITLG-KIT (Wu et al, 2000). S73 phosphorylation has been suggested to increase the transcription factor activity of MITF-M and promote its interaction with EP300/CBP (Price et al, 1998, Xu et al, 2000). In contrast, other studies have not reported increased interaction with EP300 upon S73 phosphorylation (Sato et al, 1997). S73 phosphorylation primes MITF-M for subsequent phosphorylation by GSK3B at S69, targeting it for nuclear export (Ngeow et al, 2018, reviewed in Goding and Arnheiter, 2019). This has led to a model where signaling through SCF-KIT leads to an S73-dependent increase in MITF-M signaling followed by subsequent downregulation by virtue of nuclear export and/or degradation (reviewed in Goding and Arnheiter, 2019).
KITLG-KIT signaling is implicated in melanocyte differentiation and survival during development. Mutations in the W locus in mouse, where KIT is located, are characterized by macrocytic anemia, lack of hair pigmentation and sterility, and mutations in this region or in the KIT ligand affect proliferation and migration of cell during early embryogenesis (Chabot et al, 1988; Copeland et al, 1990; Geissler et al, 1998). KIT is expressed in melanoblast precursors and contributes to their survival and migration. Consistent with this, KIT mutants do not develop the normal number of melanocytes (Wehrle-Haller and Weston, 1995; Wehrle-Haller et al, 2001; Tabone-Eglinger et al, 2012; Kunisada et al, 1998; reviewed in White and Zon, 2008).
Expression of KIT and MITF appear to be interconnected during embryogenesis in a manner that is not totally elucidated. Although the initial expression of MITF does not appear to depend on activated KIT signaling, KIT signaling does increase the transcriptional activity of MITF, and contributes to the expression of some MITF-M target genes (Hou et al, 2000; Price et al, 1998, Wu et al, 2000, Hemesath et al, 1998). Similarly, MITF expression has been shown to upregulate KIT expression in some systems (Tsujimura et al, 1996; Opdecamp et al, 1997; reviewed in Hou and Pavan, 2008).
Identifier: R-HSA-9825835
Species: Homo sapiens
Compartment: nucleoplasm
MITF binds to an E-box element in the promoter of the CDKN1A gene as assessed by EMSA and ChIP in melanoma cells (Carreira et al, 2005). MITF binding stimulates CDKN1A expression in an E-box-dependent manner as demonstrated by reporter gene assay (Carreira et al, 2005). The CDKN1A gene encodes the G1 cyclin-dependent kinase inhibitor p21. CDKN1A activity is upregulated in cells with high levels of overall MITF activity and promotes exit from the cell cycle and activation of the MITF-dependent differentiation program (Carreira et al, 2005).
The identification of the cell cycle inhibitor CDKN1A as an MITF target gene is somewhat at odds with the early characterization of MITF as a proliferative factor and its designation as a lineage survival oncogene (Widlund et al, 2002; Garraway et al, 2005). This paradox is explained by the rheostat model of MITF action (Carreira et al, 2006; reviewed in Goding and Arnheiter, 2019). In this model, cells with low overall levels of MITF activity exhibit a stem-cell-like phenotype, characterized by a low proliferation rate imposed by CDKN1B (p27kip1)-mediated cell cycle arrest, and high invasive potential by virtue of reorganization of the actin cytoskeleton and expression of matrix metalloproteases (Carreira et al, 2006). Cells with intermediate levels of MITF activity escape CDKN1B-imposed restraint on proliferation, while higher levels of MITF activity result in resumed cell-cycle arrest dependent on CDKN1A/p21 or the CDKN2A gene protein product p16 and a differentiation/pigmentation phenotype (Loercher et al, 2005; Carreira et al, 2005).
Identifier: R-HSA-9825756
Species: Homo sapiens
Compartment: nucleoplasm
MITF binds to an E-box element in the promoter of the BCL2 gene in melanocytes and melanoma cells as assessed by ChIP and EMSA, and upregulates its expression (McGill et al, 2002). BCL2 is an anti-apoptotic factor and consistent with this, overexpression of BCL2 reverses the apoptotic death seen in a dominant negative MITF melanoma cell background (McGill et al, 2002; reviewed in Goding and Arnheiter, 2019; Cheli et al, 2010).
Overexpression of BCL2 in melanoma cells lines reduces miR-211 expression and decreased MITF occupancy at promoters of target genes such as MLANA and TRPM1 (De Luca et al, 2016). A direct interaction was demonstrated between MITF and BCL2 in melanoma cells overexpressing BCL2, but with no change in MITF mRNA or protein levels. Instead, overexpression of BCL2 resulted in a significant decrease in the proportion of MITF localized to the nucleus (De Luca et al, 2016).
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