Melanocyte differentiation and mechanosensation are differentially modulated by distinct extracellular matrix proteins.

Melanocyte dysfunctions can lead to pigmentation disorders or melanoma. Melanocytes interact context-dependently with various types of ECM, including collagens and fibronectin. Alterations in ECM composition and stiffness can impact cell behavior, but their specific roles for melanocyte functions remain unclear. We here exposed melanocytes to different ECM proteins and varying substrate stiffnesses, and identified MITF, a key regulator of melanocyte differentiation and function, as an ECM- and mechanosensitive transcription factor. Moreover, distinct ECM proteins and substrate stiffness engaged a FAK/MEK/ERK/MITF signaling axis to control melanocyte functions. Collagen I restricted FAK and ERK activation, promoting elevated nuclear MITF levels, melanocyte proliferation and a differentiated transcriptomic signature. Conversely, fibronectin elicited FAK and ERK activation, reduced nuclear MITF, increased motility and a dedifferentiated transcriptomic signature. On fibronectin, inhibiting MEK/ERK activity caused increased MITF nuclear localization and enhanced melanogenesis. Additionally, FAK inhibition reduced ERK activation and enhanced melanogenesis, supporting that FAK acts upstream of ERK. Finally, melanocytes show ECM-dependent mechanoresponses. In summary, extrinsic cues exert substantial effects on melanocyte function, involving ERK-dependent MITF regulation.