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WNT5A-induced activation of the protein kinase C substrate MARCKS is required for melanoma cell invasion

Mohapatra, Purusottam LU ; Yadav, Vikas LU ; Toftdahl, Maren LU and Andersson, Tommy LU (2020) In Cancers 12(2).
Abstract

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 WNT5A expression, MARCKS 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... (More)

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 WNT5A expression, MARCKS 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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Invasion, MANS peptide, MARCKS, Melanoma, Phosphorylation, WNT5A
in
Cancers
volume
12
issue
2
article number
346
publisher
Multidisciplinary Digital Publishing Institute (MDPI)
external identifiers
  • pmid:32033033
  • scopus:85079240540
ISSN
2072-6694
DOI
10.3390/cancers12020346
language
English
LU publication?
yes
id
29b3bff6-2c2d-4634-879c-f59b6f746162
date added to LUP
2020-02-20 14:03:44
date last changed
2020-03-16 12:22:18
@article{29b3bff6-2c2d-4634-879c-f59b6f746162,
  abstract     = {<p>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 WNT5A expression, MARCKS 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.</p>},
  author       = {Mohapatra, Purusottam and Yadav, Vikas and Toftdahl, Maren and Andersson, Tommy},
  issn         = {2072-6694},
  language     = {eng},
  month        = {02},
  number       = {2},
  publisher    = {Multidisciplinary Digital Publishing Institute (MDPI)},
  series       = {Cancers},
  title        = {WNT5A-induced activation of the protein kinase C substrate MARCKS is required for melanoma cell invasion},
  url          = {http://dx.doi.org/10.3390/cancers12020346},
  doi          = {10.3390/cancers12020346},
  volume       = {12},
  year         = {2020},
}