Abstract
DOC-2/DAB2 is a potent tumor suppressor in many cancer types including prostate cancer. In prostate cancer, expression of DOC-2/DAB2 can inhibit its growth. Our recent studies demonstrate that DOC-2/DAB2 can suppress both protein kinase C and peptide growth factor-elicited signal pathways via the Ras-mitogen-activated protein kinase pathway. In this study, we further showed that the proline-rich domain of DOC-2/DAB2 could also interact with proteins containing the Src homology 3 domain, such as Src and Fgr. The binding of c-Src to DOC-2/DAB2 was enhanced in cells treated with growth factor, and this interaction resulted in c-Src inactivation. The c-Src inactivation was evidenced by the decreased tyrosine 416 phosphorylation of c-Src and reduced downstream effector activation. It appears that DOC-2/DAB2 can bind to Src homology 3 domain of c-Src and maintain it in an inactive conformation. Thus, this study provides a new mechanism for modulating c-Src in prostatic epithelium and cancer.
Highlights
The phosphorylation of DOC-2/DAB2 can be induced by several stimuli, such as growth factors and protein kinase C activator-TPA.1 We demonstrate that the serine 24 phosphorylation in the N terminus of DOC-2/DAB2 is required for its inhibitory effect on TPA-induced gene transcription [5]
DIP1/2 protein is a new member of the Ras-GAP family, and its activity can be enhanced by interacting with DOC-2/DAB2 in prostate cancer (PCa) cells treated with TPA [7], which results in inhibiting TPA-induced gene transcription and cell growth
We found that the SH3 domain in c-Src, a non-receptor tyrosine kinase, could interact with the first proline-rich domain of DOC-2/DAB2, and the amount of DOC-2/DAB2/c-Src complex was accumulated in PCa cells shortly treated with epidermal growth factor (EGF)
Summary
The phosphorylation of DOC-2/DAB2 can be induced by several stimuli, such as growth factors and protein kinase C activator-TPA.1 We demonstrate that the serine 24 phosphorylation in the N terminus of DOC-2/DAB2 is required for its inhibitory effect on TPA-induced gene transcription [5]. DIP1/2 protein is a new member of the Ras-GAP family, and its activity can be enhanced by interacting with DOC-2/DAB2 in prostate cancer (PCa) cells treated with TPA [7], which results in inhibiting TPA-induced gene transcription and cell growth. We found that the SH3 domain in c-Src, a non-receptor tyrosine kinase, could interact with the first proline-rich domain (amino acid 619 – 627) of DOC-2/DAB2, and the amount of DOC-2/DAB2/c-Src complex was accumulated in PCa cells shortly treated with EGF.
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