The prolyl isomerase Pin1 enhances HER-2 expression and cellular transformation via its interaction with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1.

Abstract

The HER-2 oncogene, a member of the erythroblastosis oncogene B (ERBB)-like oncogene family, has been shown to be amplified in many types of cancer, including breast cancer. However, the molecular mechanism of HER-2 overexpression is not completely understood. The phosphorylation of proteins on the serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is specifically catalyzed by the prolyl isomerase Pin1 and is a key signaling mechanism in cell proliferation and transformation. Here, we found that Pin1 interacts with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) protein kinase 1, resulting in the induction of HER-2 expression. Pin1(-/-) mouse embryonic fibroblasts exhibited a decrease in epidermal growth factor (EGF)-induced MEK1/2 phosphorylation compared with Pin1(+/+) mouse embryonic fibroblast. In addition, a knockdown of Pin1 resulted in the inhibition of MEK1/2 phosphorylation induced by EGF in MCF-7 cells. Furthermore, PD98059, a specific inhibitor of MEK1/2, and Juglone, a potent Pin1 inhibitor, markedly suppressed the expression of activator protein-2alpha and the HER-2 promoter activity induced by EGF or 12-O-tetradecanoylphorbol-13-acetate in MCF-7 cells. Importantly, these inhibitors inhibited the neoplastic cell transformation induced by EGF in Pin1-overexpressing JB6 Cl41 cells, which showed enhanced cellular formation compared with the control cells. Therefore, Juglone and PD98059 inhibited the colony formation of MCF-7 breast cancer cells in soft agar. These results indicate that Pin1 amplifies EGF signaling in breast cancer cells through its interaction with MEK1 and then enhances HER-2 expression, suggesting that Pin1 plays an important role in the overexpression of HER-2 through Pin1-MEK1-activator protein-2alpha signaling in breast cancer.

• Authors: Prem Khanal, Gwang Mo Namgoong, Bong Seok Kang, Eun-Rhan Woo, Hong Seok Choi
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 3 Pg. 606-16 (Mar 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20179161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NIMA-Interacting Peptidylprolyl Isomerase
• Epidermal Growth Factor
• MAP2K2 protein, human
• ERBB2 protein, human
• Receptor, ErbB-2
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human
• PIN1 protein, human
• Peptidylprolyl Isomerase
• Pin1 protein, mouse

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Cells, Cultured
• Epidermal Growth Factor (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MAP Kinase Kinase 1 (metabolism, physiology)
• MAP Kinase Kinase 2 (metabolism, physiology)
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinase 3 (metabolism, physiology)
• NIMA-Interacting Peptidylprolyl Isomerase
• Peptidylprolyl Isomerase (genetics, metabolism, physiology)
• Phosphorylation
• Protein Binding (physiology)
• Receptor, ErbB-2 (genetics, metabolism)
• Up-Regulation (genetics, physiology)