WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion
WNT5A is a well-known mediator of melanoma cell invasion and metastasis via its ability to activate protein kinase C (PKC), which is monitored by phosphorylation of the endogenous PKC substrate myristoylated alanine-rich c-kinase substrate (MARCKS). However, a possible direct contribution of MARCKS...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/2/346 |
| _version_ | 1797709198496104448 |
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| author | Purusottam Mohapatra Vikas Yadav Maren Toftdahl Tommy Andersson |
| author_facet | Purusottam Mohapatra Vikas Yadav Maren Toftdahl Tommy Andersson |
| author_sort | Purusottam Mohapatra |
| collection | DOAJ |
| description | WNT5A is a well-known mediator of melanoma cell invasion and metastasis via its ability to activate protein kinase C (PKC), which is monitored by phosphorylation of the endogenous PKC substrate myristoylated alanine-rich c-kinase substrate (MARCKS). However, a possible direct contribution of MARCKS in WNT5A-mediated melanoma cell invasion has not been investigated. Analyses of melanoma patient databases suggested that similar to <i>WNT5A</i> expression, <i>MARCKS</i> expression appears to be associated with increased metastasis. A relationship between the two is suggested by the findings that recombinant WNT5A (rWNT5A) induces both increased expression and phosphorylation of MARCKS, whereas WNT5A silencing does the opposite. Moreover, WNT5A-induced invasion of melanoma cells was blocked by siRNA targeting MARCKS, indicating a crucial role of MARCKS expression and/or its phosphorylation. Next, we employed a peptide inhibitor of MARCKS phosphorylation that did not affect MARCKS expression and found that it abolished WNT5A-induced melanoma cell invasion. Similarly, rWNT5A induced the accumulation of phosphorylated MARCKS in membrane protrusions at the leading edge of melanoma cells. Our results demonstrate that WNT5A-induced phosphorylation of MARCKS is not only an indicator of PKC activity but also a crucial regulator of the metastatic behavior of melanoma and therefore an attractive future antimetastatic target in melanoma patients. |
| first_indexed | 2024-03-12T06:32:53Z |
| format | Article |
| id | doaj.art-4c070b1110f8448982389d3cfdc07134 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:32:53Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4c070b1110f8448982389d3cfdc071342023-09-03T01:29:56ZengMDPI AGCancers2072-66942020-02-0112234610.3390/cancers12020346cancers12020346WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell InvasionPurusottam Mohapatra0Vikas Yadav1Maren Toftdahl2Tommy Andersson3Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Skåne University Hospital, Lund University, SE-202 13 Malmö, SwedenCell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Skåne University Hospital, Lund University, SE-202 13 Malmö, SwedenCell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Skåne University Hospital, Lund University, SE-202 13 Malmö, SwedenCell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Skåne University Hospital, Lund University, SE-202 13 Malmö, SwedenWNT5A is a well-known mediator of melanoma cell invasion and metastasis via its ability to activate protein kinase C (PKC), which is monitored by phosphorylation of the endogenous PKC substrate myristoylated alanine-rich c-kinase substrate (MARCKS). However, a possible direct contribution of MARCKS in WNT5A-mediated melanoma cell invasion has not been investigated. Analyses of melanoma patient databases suggested that similar to <i>WNT5A</i> expression, <i>MARCKS</i> expression appears to be associated with increased metastasis. A relationship between the two is suggested by the findings that recombinant WNT5A (rWNT5A) induces both increased expression and phosphorylation of MARCKS, whereas WNT5A silencing does the opposite. Moreover, WNT5A-induced invasion of melanoma cells was blocked by siRNA targeting MARCKS, indicating a crucial role of MARCKS expression and/or its phosphorylation. Next, we employed a peptide inhibitor of MARCKS phosphorylation that did not affect MARCKS expression and found that it abolished WNT5A-induced melanoma cell invasion. Similarly, rWNT5A induced the accumulation of phosphorylated MARCKS in membrane protrusions at the leading edge of melanoma cells. Our results demonstrate that WNT5A-induced phosphorylation of MARCKS is not only an indicator of PKC activity but also a crucial regulator of the metastatic behavior of melanoma and therefore an attractive future antimetastatic target in melanoma patients.https://www.mdpi.com/2072-6694/12/2/346melanomainvasionwnt5amarcksphosphorylationmans peptide |
| spellingShingle | Purusottam Mohapatra Vikas Yadav Maren Toftdahl Tommy Andersson WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion Cancers melanoma invasion wnt5a marcks phosphorylation mans peptide |
| title | WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion |
| title_full | WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion |
| title_fullStr | WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion |
| title_full_unstemmed | WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion |
| title_short | WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion |
| title_sort | wnt5a induced activation of the protein kinase c substrate marcks is required for melanoma cell invasion |
| topic | melanoma invasion wnt5a marcks phosphorylation mans peptide |
| url | https://www.mdpi.com/2072-6694/12/2/346 |
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