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Recognition of CD146 as an ERM-binding protein offers novel mechanisms for melanoma cell migration

Oncogene volume 31, pages 306–321 (2012)Cite this article

Abstract

Tumor cell migration is a well-orchestrated multistep process that drives cancer development and metastasis. Previous data indicated that CD146 expression correlates with malignant progression and metastatic potential of human melanoma cells. However, the exact molecular mechanism of how CD146 promotes melanoma cell migration still remains poorly understood. Here, we report that CD146 physically interacts with actin-linking ezrin–radixin–moesin (ERM) proteins and recruits ERM proteins to cell protrusions, promoting the formation and elongation of microvilli. Moreover, CD146-promoted melanoma cell migration is linked to RhoA activation and ERM phosphorylation. CD146 recruits Rho guanine nucleotide dissociation inhibitory factors 1 (RhoGDI1) through ERM proteins and thus sequesters RhoGDI1 from RhoA, which leads to upregulated RhoA activity and increased melanoma cell motility. CD146-activated RhoA also promotes further ERM phosphorylation and activation through Rho-phosphatidylinositol-4-phosphate-5-kinase-phosphatidylinositol 4,5-biphosphate pathway, which reinforces CD146/ERM association. Thus, our results provide a mechanistic basis to understand the role of CD146 in regulating human melanoma cell motility.

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Abbreviations

ERM proteins:

ezrin–radixin–moesin proteins

PIP2:

phosphatidylinositol 4,5-biphosphate

RBD:

Rho-binding domain

RhoGDI1:

Rho guanine nucleotide dissociation inhibitory factors 1

ROCK:

Rho-associated coiled-coil protein kinase

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Acknowledgements

We thank Dr J Johnson for providing the CD146-transfected Mel-888CD146 cells and CD146 gene contained in pUC-CD146 plasmids. This work is partly supported by grants from the National 863 Grant (2006AA02A245), the National Basic Research Program of China (973 Program) (2009CB521704, 2011CB933503), the National Important Science and Technology Specific Projects (2008ZX10004-005, 2008ZX10002-017, 2009ZX09102-247), the National Natural Science Foundation of China (91029732) and the Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-YW-R-121, KSCX2-YW-R-173, KSCX2-YW-M15).

Author contributions: YL and CZ designed, carried out experiments, analyzed data and wrote the paper. JZ performed experiments and carried out image analyses. DL, JZ and SX contributed to experimental design, data analysis and expertise. JF and DY contributed to experimental design and data analysis. XY designed the project, designed experiments and analyzed data.

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  1. Y Luo and C Zheng: These authors contributed equally to this work.

Authors and Affiliations

  1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Y Luo, C Zheng, J Zhang, D Lu, J Zhuang, S Xing, J Feng, D Yang & X Yan

  2. Chinese Academy of Sciences,

    Y Luo, C Zheng, J Zhang, D Lu, J Zhuang, S Xing, J Feng, D Yang & X Yan

  3. University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Y Luo, C Zheng, J Zhang, D Lu, J Zhuang, S Xing, J Feng, D Yang & X Yan

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Luo, Y., Zheng, C., Zhang, J. et al. Recognition of CD146 as an ERM-binding protein offers novel mechanisms for melanoma cell migration. Oncogene 31, 306–321 (2012). https://doi.org/10.1038/onc.2011.244

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