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

Mol Cell. 2002 May;9(5):993-1004. doi: 10.1016/s1097-2765(02)00510-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis*
  • Breast / metabolism
  • Breast / pathology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • CDC2 Protein Kinase / 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*
  • cdc25 Phosphatases / metabolism


  • Antineoplastic Agents, Phytogenic
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin B
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Tyrosine
  • Receptor, ErbB-2
  • CDC2 Protein Kinase
  • CDC25C protein, human
  • cdc25 Phosphatases
  • Paclitaxel