title: NEDD9 and BCAR1 negatively regulate E-cadherin membrane localization, and promote E-cadherin degradation.
abstract: The Cas scaffolding proteins (NEDD9/HEF1/CAS-L, BCAR1/p130Cas, EFSSIN, and HEPL/CASS4) regulate cell migration, division and survival, and are often deregulated in cancer. High BCAR1 expression is linked to poor prognosis in breast cancer patients, while upregulation of NEDD9 contributes to the metastatic behavior of melanoma and glioblastoma cells. Our recent work knocking out the single Drosophila Cas protein, Dcas, identified a genetic interaction with E-cadherin. As E-cadherin is often downregulated during epithelial-mesenchymal transition (EMT) prior to metastasis, if such an activity was conserved in mammals it might partially explain how Cas proteins promote aggressive tumor behavior. We here establish that Cas proteins negatively regulate E-cadherin expression in human mammary cells. Cas proteins do not affect E-cadherin transcription, but rather, BCAR1 and NEDD9 signal through SRC to promote E-cadherin removal from the cell membrane and lysosomal degradation. We also find mammary tumors arising in MMTV-polyoma virus T-antigen mice have enhanced junctional E-cadherin in a Nedd9(-/-) background. Cumulatively, these results suggest a new role for Cas proteins in cell-cell adhesion signaling in cancer.
authors.affiliation: Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Tikhmyanova
authors.forename: Erica A
authors.initials: EA
authors.lastname: Golemis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C493841:BCAR1 protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D050719:Crk-Associated Substrate Protein; D003902:Detergents; C577585:Fzr1 protein, mouse; C099942:NEDD9 protein, human; C505592:NEDD9 protein, mouse; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D019061:src-Family Kinases