The most critical transcription factor that regulates melanocyte function is microphthalmia transcription factor (MITF).

MITF is a member of the basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors conserved in essentially all vertebrate species.

The M-MITF isoform is considered as a master regulator of differentiation of the melanocyte lineage and is induced through the cAMP pathway.

It is believed that upon stimulatory binding of α-melanocyte stimulating hormone (α-MSH) to the melanocortin 1 receptor (MC1R), adenyl cyclase is activated and cAMP produced. cAMP then activates the protein kinase A (PKA) pathway to phosphorylate cAMP-responsive element binding protein (CREB) transcription factors, which mediates MITF-M promoter activation to induce melanogenesis.

MITF is also regulated at the transcriptional level by interleukin-6 (IL-6) and Wnt Signaling pathway.

Furthermore, MITF is post-transcriptionally regulated by phosphorylation via ribosomal S6 kinase (RSK), glycogen synthase kinase-3b (GSK3b), p38 stress signaling and mitogen-activated protein kinase (MAPK) pathways by currently undefined mechanisms/pathways.

As MITF is considered an important regulator of melanogenesis, manipulation of the aforementioned signalling pathways may have potential therapeutic use.

MITF is located in the center of multiple signalling pathways which control differentiation, morphology, proliferation and survival of the various cells of the melanocyte lineage: melanoblasts, melanocytes and melanoma.

MITF plays a major role in melanoblast differentiation, by inducing the key enzyme of melanogenesis, tyrosinase, and its secondary enzymes, Tyrp1 and Dct.

MITF regulates morphology and migration of melanocytes, particularly by regulating cytoskeleton organisation and cell-cell adhesion.  

A number of biological compounds, including transforming growth factor (TGF-β1), tumor necrosis factor (TNFα) interleukins 1 and 6 (IL-1, IL6), dickkopf 1 (DKK1), calpain inhibitors, lysophosphatidic acid and C2 ceramides, are able to inhibit the function of tyrosinase and related enzymes (TYRP1 and DCT), mainly through down-regulation of MITF.

In addition to the process of melanization, MITF also regulates melanocyte differentiation, development, and survival Pertaining to survival, MITF regulates the anti-apoptotic molecule Bcl-2 as well as additional survival genes.

It has recently been demonstrated that melanocytes deficient in MITF expression are compromised in their resistance to UV-induced apoptosis. Therefore, caution is warranted when attempting to decrease skin pigmentation by down-regulating MITF since melanocyte death may be a consequence.