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-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.
Tan
Ming
M
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Jing
Tong
T
Lan
Keng-Hsueh
KH
Neal
Christopher L
CL
Li
Ping
P
Lee
Sangkyou
S
Fang
Dexing
D
Nagata
Yoichi
Y
Liu
Jiaxin
J
Arlinghaus
Ralph
R
Hung
Mien-Chie
MC
Yu
Dihua
D
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
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