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Simple Summary: Melanoma is a growing health issue in the 21st century. Due to early metastasis and the development of resistance, it still goes along with a poor prognosis. ADCK protein kinases have been shown to play a role during cancer development and metastasis. Here, we investigated the role of ADCK2 in melanoma. In our study, we showed that higher levels of intratumoral ADCK2 benefit patient survival, while a low expression of ADCK2 was associated with a higher motility and a dedifferentiated state of melanoma cells, which facilitates metastasis. Our results could give new insights into melanoma metastasis, and ADCK2 could qualify as a prognostic marker or a target for melanoma therapy in the future. Background: ADCK2 is a member of the AarF domain-containing kinase family, which consists of five members, and has been shown to play a role in CoQ metabolism. However, ADCKs have also been connected to cancer cell survival, proliferation and motility. In this study, we investigated the role of ADCK2 in melanoma. Methods: The effect of ADCK2 on melanoma cell motility was evaluated by a scratch assay and a transwell invasion assay upon siRNA-mediated knockdown or stable overexpression of ADCK2. Results: We found that high levels of intratumoral ADCK2 and MYL6 are associated with a higher survival rate in melanoma patients. Knocking down ADCK2 resulted in enhanced cell migration of melanoma cells. Moreover, ADCK2-knockdown cells adopted a more dedifferentiated phenotype. A gene expression array revealed that the expression of ADCK2 correlated with the expressions of MYL6 and RAB2A. Knocking down MYL6 in ADCK2-overexpressing cells could abrogate the effect of ADCK2 overexpression and thus confirm the functional connection between ADCK2 and MYL6. Conclusion: ADCK2 affects melanoma cell motility, most probably via MYL6. Our results allow the conclusion that ADCK2 could act as a tumor suppressor in melanoma. [ABSTRACT FROM AUTHOR]