Phosphorylation on tyrosine-15 of p34(Cdc2) by ErbB2 inhibits p34(Cdc2) activation and is involved in resistance to taxol-induced apoptosis

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-over...

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Bibliographic Details
Published in:Molecular cell 2002-05, Vol.9 (5), p.993-1004
Main Authors: Tan, Ming, Jing, Tong, Lan, Keng-Hsueh, Neal, Christopher L, Li, Ping, Lee, Sangkyou, Fang, Dexing, Nagata, Yoichi, Liu, Jiaxin, Arlinghaus, Ralph, Hung, Mien-Chie, Yu, Dihua
Format: Article
Language:English
Subjects:
Antineoplastic Agents, Phytogenic - pharmacology
Apoptosis
Breast - metabolism
Breast - pathology
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
CDC2 Protein Kinase - metabolism
cdc25 Phosphatases - metabolism
Cell Cycle Proteins - metabolism
Cells, Cultured
Cyclin B - metabolism
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - metabolism
DNA Fragmentation
Drug Resistance, Neoplasm
Female
Humans
In Situ Nick-End Labeling
Mitosis
Paclitaxel - pharmacology
Phosphorylation
Receptor, ErbB-2 - metabolism
Tumor Cells, Cultured
Tyrosine - metabolism
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Summary: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.
ISSN:1097-2765
DOI:10.1016/S1097-2765(02)00510-5