Negative regulation of HER2 signaling by the PEST-type protein-tyrosine phosphatase BDP1.
Signaling by receptor tyrosine kinases (RTK) mediates a variety of complex cellular functions and in case of deregulation can contribute to pathophysiological processes. A tight and finely tuned control of RTK activity is therefore critical for the cell. We investigated the role of the PEST-type protein-tyrosine phosphatase BDP1 in the regulation of HER2, a member of the epidermal growth factor receptor (EGFR) family of RTKs. Here we demonstrate that HER2 signaling is highly sensitive to BDP1 activity. Overexpression of BDP1 inhibited ligand-induced activation of HER2 but not that of the closely related EGFR. On the other hand, suppression of endogenous BDP1 expression increased the phosphorylation state of HER2. In addition, BDP1 was able to interfere with downstream signaling events by inhibiting the phosphorylation of the adaptor protein Gab1 and reducing mitogen-activated protein kinase activation. Supported by the finding that BDP1 is coexpressed with HER2 in breast cancer cells, we suggest that BDP1 is an important regulator of HER2 activity and thus the first protein-tyrosine phosphatase shown to be involved in HER2 signal attenuation.
Gensler
Miriam
M
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, Germany.
Buschbeck
Marcus
M
Ullrich
Axel
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D066246:ErbB Receptors; D008024:Ligands; D010750:Phosphoproteins; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D025521:Tumor Suppressor Proteins; C098587:GAB1 protein, human; C490897:Gab1 protein, mouse; C422224:PTPN18 protein, human