title: Phosphorylation on tyrosine-15 of p34(Cdc2) by ErbB2 inhibits p34(Cdc2) activation and is involved in resistance to taxol-induced apoptosis.
abstract: ErbB2 overexpression confers resistance to taxol-induced apoptosis by inhibiting p34(Cdc2) activation. One mechanism is via ErbB2-mediated upregulation of p21(Cip1), which inhibits Cdc2. Here, we report that the inhibitory phosphorylation on Cdc2 tyrosine (Y)15 (Cdc2-Y15-p) is elevated in ErbB2-overexpressing breast cancer cells and primary tumors. ErbB2 binds to and colocalizes with cyclin B-Cdc2 complexes and phosphorylates Cdc2-Y15. The ErbB2 kinase domain is sufficient to directly phosphorylate Cdc2-Y15. Increased Cdc2-Y15-p in ErbB2-overexpressing cells corresponds with delayed M phase entry. Expressing a nonphosphorylatable mutant of Cdc2 renders cells more sensitive to taxol-induced apoptosis. Thus, ErbB2 membrane RTK can confer resistance to taxol-induced apoptosis by directly phosphorylating Cdc2.
authors.affiliation: Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
authors.forename: Tong
authors.initials: T
authors.lastname: Jing
authors.forename: Keng-Hsueh
authors.initials: KH
authors.lastname: Lan
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Neal
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Sangkyou
authors.initials: S
authors.lastname: Lee
authors.forename: Dexing
authors.initials: D
authors.lastname: Fang
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nagata
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Liu
authors.forename: Ralph
authors.initials: R
authors.lastname: Arlinghaus
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D019926:Cyclin B / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008938:Mitosis; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine; D020687:cdc25 Phosphatases; C493956:CDKN1A protein, human; C517009:CDC25C protein, human