4.5 Article

Pacsin 2-dependent N-cadherin internalization regulates the migration behaviour of malignant cancer cells

Journal

JOURNAL OF CELL SCIENCE
Volume 136, Issue 10, Pages -

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.260827

Keywords

N-cadherin; Pacsin 2; Dynamin 2; Endocytosis; Collective cell migration

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This study demonstrates that the BAR domain protein pacsin 2 plays a crucial role in collective cell migration by regulating the endocytosis of N-cadherin in human cancer cells. Depletion of pacsin 2 leads to the formation of cell-cell contacts enriched with N-cadherin and directed cell migration. Furthermore, pacsin 2-depleted cells show impaired internalization of N-cadherin from the cell surface, indicating a new endocytic route for N-cadherin in collective cell migration and suggesting pacsin 2 as a potential therapeutic target for cancer metastasis.
Collective cell migration is the coordinated movement of multiple cells connected by cadherin-based adherens junctions and is essential for physiological and pathological processes. Cadherins undergo dynamic intracellular trafficking, and their surface level is determined by a balance between endocytosis, recycling and degradation. However, the regulatory mechanism of cadherin turnover in collective cell migration remains elusive. In this study, we show that the Bin/amphiphysin/Rvs (BAR) domain protein pacsin 2 (protein kinase C and casein kinase substrate in neurons protein 2) plays an essential role in collective cell migration by regulating N-cadherin (also known as CDH2) endocytosis in human cancer cells. Pacsin 2-depleted cells formed cell-cell contacts enriched with N-cadherin and migrated in a directed manner. Furthermore, pacsin 2-depleted cells showed attenuated internalization of N-cadherin from the cell surface. Interestingly, GST pull-down assays demonstrated that the pacsin 2 SH3 domain binds to the cytoplasmic region of N-cadherin, and expression of an N-cadherin mutant defective in binding to pacsin 2 phenocopied pacsin 2 RNAi cells both in cell contact formation and N-cadherin endocytosis. These data support new insights into a novel endocytic route of N-cadherin in collective cell migration, highlighting pacsin 2 as a possible therapeutic target for cancer metastasis.

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