The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway is frequently deregulated in cancer. Downstream of PI3K, Akt1 and Akt2 have opposing roles in breast cancer invasive migration, leading to metastatic dissemination. Here, we identify palladin, an actin-associated protein, as an Akt1-specific substrate that modulates breast cancer cell invasive migration. Akt1, but not Akt2, phosphorylates palladin at Ser507 in a domain that is critical for F-actin bundling. Downregulation of palladin enhances migration and invasion of breast cancer cells and induces abnormal branching morphogenesis in 3D cultures. Palladin phosphorylation at Ser507 is required for Akt1-mediated inhibition of breast cancer cell migration and also for F-actin bundling, leading to the maintenance of an organized actin cytoskeleton. These findings identify palladin as an Akt1-specific substrate that regulates cell motility and provide a molecular mechanism that accounts for the functional distinction between Akt isoforms in breast cancer cell signaling to cell migration.
Chin
Y Rebecca
YR
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Toker
Alex
A
D000199:Actins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D048430:Cell Shape; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012694:Serine; D015398:Signal Transduction; D018874:Spheroids, Cellular; D013379:Substrate Specificity; D014162:Transfection
D000199:Actins; D003598:Cytoskeletal Proteins; C412722:PALLD protein, human; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D012694:Serine; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt
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