Interplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis. 2019

Tao Han, and Shulong Jiang, and Hong Zheng, and Qing Yin, and Mengyu Xie, and Margaret R Little, and Xiu Yin, and Ming Chen, and Su Jung Song, and Amer A Beg, and Pier Paolo Pandolfi, and Lixin Wan
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.

The Anaphase Promoting Complex (APC) coactivator Cdh1 drives proper cell cycle progression and is implicated in the suppression of tumorigenesis. However, it remains elusive how Cdh1 restrains cancer progression and how tumor cells escape the inhibition of Cdh1. Here we report that Cdh1 suppresses the kinase activity of c-Src in an APC-independent manner. Depleting Cdh1 accelerates breast cancer cell proliferation and cooperates with PTEN loss to promote breast tumor progression in mice. Hyperactive c-Src, on the other hand, reciprocally inhibits the ubiquitin E3 ligase activity of APCCdh1 through direct phosphorylation of Cdh1 at its N-terminus, which disrupts the interaction between Cdh1 and the APC core complex. Furthermore, pharmacological inhibition of c-Src restores APCCdh1 tumor suppressor function to repress a panel of APCCdh1 oncogenic substrates. Our findings reveal a reciprocal feedback circuit of Cdh1 and c-Src in the crosstalk between the cell cycle machinery and the c-Src signaling pathway.

UI MeSH Term Description Entries
D009368 Neoplasm Transplantation Experimental transplantation of neoplasms in laboratory animals for research purposes. Transplantation, Neoplasm,Neoplasm Transplantations,Transplantations, Neoplasm
D001943 Breast Neoplasms Tumors or cancer of the human BREAST. Breast Cancer,Breast Tumors,Cancer of Breast,Breast Carcinoma,Cancer of the Breast,Human Mammary Carcinoma,Malignant Neoplasm of Breast,Malignant Tumor of Breast,Mammary Cancer,Mammary Carcinoma, Human,Mammary Neoplasm, Human,Mammary Neoplasms, Human,Neoplasms, Breast,Tumors, Breast,Breast Carcinomas,Breast Malignant Neoplasm,Breast Malignant Neoplasms,Breast Malignant Tumor,Breast Malignant Tumors,Breast Neoplasm,Breast Tumor,Cancer, Breast,Cancer, Mammary,Cancers, Mammary,Carcinoma, Breast,Carcinoma, Human Mammary,Carcinomas, Breast,Carcinomas, Human Mammary,Human Mammary Carcinomas,Human Mammary Neoplasm,Human Mammary Neoplasms,Mammary Cancers,Mammary Carcinomas, Human,Neoplasm, Breast,Neoplasm, Human Mammary,Neoplasms, Human Mammary,Tumor, Breast
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D016392 Proto-Oncogene Proteins pp60(c-src) Membrane-associated tyrosine-specific kinases encoded by the c-src genes. They have an important role in cellular growth control. Truncation of carboxy-terminal residues in pp60(c-src) leads to PP60(V-SRC) which has the ability to transform cells. This kinase pp60 c-src should not be confused with csk, also known as c-src kinase. c-src Protein pp60,pp60(c-src),src Proto-Oncogene Protein pp60,Phosphoprotein pp60(c-src),Proto-Oncogene Protein pp60(c-src),Proto-Oncogene Protein src,pp60 c-src,src Proto-Oncogene Product,Protein pp60, c-src,Protein src, Proto-Oncogene,Proto Oncogene Protein src,Proto-Oncogene Product, src,c src Protein pp60,c-src, pp60,pp60 c src,pp60, c-src Protein,src Proto Oncogene Product,src Proto Oncogene Protein pp60
D044767 Ubiquitin-Protein Ligases A diverse class of enzymes that interact with UBIQUITIN-CONJUGATING ENZYMES and ubiquitination-specific protein substrates. Each member of this enzyme group has its own distinct specificity for a substrate and ubiquitin-conjugating enzyme. Ubiquitin-protein ligases exist as both monomeric proteins multiprotein complexes. Ubiquitin-Protein Ligase,E3 Ligase,E3 Ubiquitin Ligase,Ubiquitin Ligase E3,Ubiquitin-Protein Ligase E3,Ligase E3, Ubiquitin,Ligase E3, Ubiquitin-Protein,Ligase, E3,Ligase, E3 Ubiquitin,Ligase, Ubiquitin-Protein,Ligases, Ubiquitin-Protein,Ubiquitin Ligase, E3,Ubiquitin Protein Ligase,Ubiquitin Protein Ligase E3,Ubiquitin Protein Ligases
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D049109 Cell Proliferation All of the processes involved in increasing CELL NUMBER including CELL DIVISION. Cell Growth in Number,Cellular Proliferation,Cell Multiplication,Cell Number Growth,Growth, Cell Number,Multiplication, Cell,Number Growth, Cell,Proliferation, Cell,Proliferation, Cellular
D051059 PTEN Phosphohydrolase A lipid phosphatase that contains a C2 DOMAIN and acts on phosphatidylinositol-3,4,5-trisphosphate to regulate various SIGNAL TRANSDUCTION PATHWAYS. It modulates CELL GROWTH PROCESSES; CELL MIGRATION; and APOPTOSIS. Mutations in PTEN are associated with COWDEN DISEASE and PROTEUS SYNDROME as well as NEOPLASTIC CELL TRANSFORMATION. MMAC1 Protein,Mutated In Multiple Advanced Cancers 1 Protein,PTEN Phosphatase,PTEN Protein,PTEN Protein Phosphatase,Phosphatase and Tensin Homologue on Chromosome Ten Protein,Phosphatase, PTEN,Phosphatase, PTEN Protein,Phosphohydrolase, PTEN,Protein Phosphatase, PTEN

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