LIM and SH3 protein 1 localizes to the leading edge of protruding lamellipodia and regulates axon development.
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ABSTRACT:
SUBMITTER: Pollitt SL
PROVIDER: S-EPMC7927181 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cell migration is initiated in response to biochemical or physical cues in the environment that promote actin-mediated lamellipodial protrusion followed by the formation of nascent integrin adhesions (NAs) within the protrusion to drive leading edge advance. Although FAK is known to be required for cell migration through effects on focal adhesions, its role in NA formation and lamellipodial dynamics is unclear. Live-cell microscopy of FAK(-/-)cells with expression of phosphorylation deficient or a FERM-domain mutant deficient in Arp2/3 binding revealed a requirement for FAK in promoting the dense formation, transient stabilization, and timely turnover of NA within lamellipodia to couple actin-driven protrusion to adhesion and advance of the leading edge. Phosphorylation on Y397 of FAK promotes dense NA formation but is dispensable for transient NA stabilization and leading edge advance. In contrast, transient NA stabilization and advance of the cell edge requires FAK-Arp2/3 interaction, which promotes Arp2/3 localization to NA and reduces FAK activity. Haptosensing of extracellular matrix (ECM) concentration during migration requires the interaction between FAK and Arp2/3, whereas FAK phosphorylation modulates mechanosensing of ECM stiffness during spreading. Taken together, our results show that mechanistically separable functions of FAK in NA are required for cells to distinguish distinct properties of their environment during migration.
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Project description:The process of tumor invasion requires degradation of extracellular matrix by proteolytic enzymes. Cancer cells form protrusive invadopodia, which produce and release matrix metalloproteinases (MMPs) to degrade the basement membrane and thereby allowing metastasis. We investigated the effect of LASP1, a newly identified protein in invadopodia, on expression, secretion and activation of MMPs in invasive breast tumor cells. By analyzing and verifying microarray data sets and performing reporter assays, we demonstrate that LASP1 positively modulates the expression of c-Fos and AP-1 activity, and thereby up-regulates expression of MMP1, -3 and -9 in breast cancer cells. Furthermore, zymography assays and Western blot analysis revealed cytosolic LASP1 promotion of MMP vesicle secretion into the extracellular matrix, thus altering the microenvironment during cancer progression. The newly identified role of LASP1 in regulating matrix degradation by affecting MMP transcription and secretion elucidated the migratory potential observed in studies that investigated the upregulation of LASP1 in aggressive cancers.
2017-02-03 | GSE77584 | GEO