Journal
CURRENT BIOLOGY
Volume 21, Issue 17, Pages 1460-1469Publisher
CELL PRESS
DOI: 10.1016/j.cub.2011.06.065
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Funding
- National Institutes of Health (NIH) [1R01-GM075126]
- American Cancer Society [RSG-118085]
- NIH [R01-GM078373]
- American Heart Association [10GRNT4230026]
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Background: Branched actin assembly is critical for both cell motility and membrane trafficking. The branched actin regulator cortactin is generally considered to promote cell migration by controlling leading-edge lamellipodial dynamics. However, recent reports indicate that lamellipodia are not required for cell movement, suggesting an alternate mechanism. Results: Because cortactin also regulates membrane trafficking and adhesion dynamics, we hypothesized that altered secretion of extracellular matrix (ECM) and/or integrin trafficking might underlie motility defects of cortactin-knockdown (KD) cells. Consistent with a primary defect in ECM secretion, both motility and lamellipodial defects of cortactin-KD cells were fully rescued by plating on increasing concentrations of exogenous ECM. Furthermore, cortactin-KD cell speed defects were rescued on cell-free autocrine ECM produced by control cells, but not on ECM produced by cortactin-KD cells. Investigation of the mechanism revealed that whereas endocytosed fibronectin (FN) is redeposited at the basal cell surface by control cells, cortactin-KD cells exhibit defective FN secretion and abnormal FN retention in a late endocytic/lysosomal compartment. Cortactin-KD motility and FN deposition defects were phenocopied by KD in control cells of the lysosomal fusion regulator synaptotagmin-7. Rescue of cortactin-KD cells by expression of cortactin-binding domain mutants revealed that interaction with the Arp2/3 complex and actin filaments is essential for rescue of both cell motility and autocrine ECM secretion phenotypes, whereas binding of SH3-domain partners is not required. Conclusions: Efficient cell motility, promoted by cortactin regulation of branched actin networks, involves processing and resecretion of internalized ECM from a late endosomal/lysosomal compartment.
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