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Papers In Press, published online ahead of print May 22, 2001
Urology, UT Southwestern Medical Center, Dallas, TX 75390-9110
Corresponding Author: JT.Hsieh{at}UTSouthwestern.edu
DOC-2/DAB2 (differentially expressed in ovarian carcinoma-2/disabled 2) appears to be a potential tumor suppressor gene with a growth inhibitory effect on several cancer types. Previously, we showed that DOC-2/DAB2 suppresses protein kinase C (PKC)-induced AP-1 activation, which is modulated by serine 24 phosphorylation in the N-terminal of DOC-2/DAB2. However, the functional impact of the C-terminal of DOC-2/DAB2, containing 3 proline-rich domains, has not been explored. In this study, we examined this functional role in modulating signaling mediated by peptide growth factor receptor tyrosine kinase (RPTK), particularly as it involves the interaction with Grb2. Using sequence specific peptides, we found that the second proline-rich domain of DOC-2/DAB2 is the key binding site to Grb2 in the presence of growth factors. Such elevated binding interrupts the binding between SOS and Grb2, which consequently suppresses downstream Erk phosphorylation. Reduced Erk phosphorylation was restored when the binding between DOC-2/DAB2 and Grb2 was interrupted by a specific peptide or by increasing the expression of Grb2. Furthermore, the C-terminal of DOC-2/DAB2 construct can inhibit the AP-1 activity elicited by growth factors. We conclude that DOC-2/DAB2, a potent negative regulator, can suppress Erk activation by interrupting the binding between Grb2 and SOS that is elicited by peptide growth factors. This study further illustrates that DOC-2/DAB2 has multiple effects on the RAS-mediated signal cascades active in cancer cells.
J. Biol. Chem, 10.1074/jbc.M102803200
Submitted on March 29, 2001
Revised on May 18, 2001
Accepted on May 22, 2001
The inhibitory role of DOC-2/DAB2 in growth factor receptors-mediated signal cascade: DOC-2/DAB2-mediated inhibition of Erk phosphorylation via binding to Grb2
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