TY - JOUR
T1 - The role of DOC-2/DAB2 protein phosphorylation in the inhibition of AP-1 activity. An underlying mechanism of its tumor-suppressive function in prostate cancer
AU - Tseng, Ching Ping
AU - Ely, Brent D.
AU - Pong, Rey Chen
AU - Wang, Zhi
AU - Zhou, Jian
AU - Hsieh, Jer Tsong
PY - 1999/11/5
Y1 - 1999/11/5
N2 - DOC-2/DAB2, a novel phosphoprotein with signal-transducing capability, inhibits human prostatic cancer cells (Tseng, C.-P., Ely, B. D., Li, Y., Pong, R.-C., and Hsieh, J.-T. (1998) Endocrinology 139, 3542-3553). However, its mechanism of action is not understood completely. This study delineates the functional significance of DOC-2/DAB2 protein phosphorylation and demonstrates that in vivo activation of protein kinase C (PKC) by 12-O- tetradecanoylphorbol-13-acetate (TPA) induces DOC-2/DAB2 phosphorylation, including a serine residue at position 24. Mutation of Ser24 to Ala reduced DOC-2/DAB2 phosphorylation by PKC. Using a synthetic Ser24 peptide (APS24KKEKKKGSEKTD) or recombinant DOC-2/DAB2 as substrates, PKCβII, PKCγ, and PKCδ (but not casein kinase II) directly phosphorylated Ser24 in vitro. This indicates that DOC-2/DAB2 is a PKC-specific substrate. Since expression of wild-type DOC-2/DAB2, but not the S24A mutant, inhibited TPA- induced AP-1 activity in prostatic epithelial cells, phosphorylation of Ser24 appears to play a critical role in modulating TPA-induced AP-1 activity. Taken together, these data suggest that PKC-regulated phosphorylation of DOC-2/DAB2 protein may help its growth inhibitory function.
AB - DOC-2/DAB2, a novel phosphoprotein with signal-transducing capability, inhibits human prostatic cancer cells (Tseng, C.-P., Ely, B. D., Li, Y., Pong, R.-C., and Hsieh, J.-T. (1998) Endocrinology 139, 3542-3553). However, its mechanism of action is not understood completely. This study delineates the functional significance of DOC-2/DAB2 protein phosphorylation and demonstrates that in vivo activation of protein kinase C (PKC) by 12-O- tetradecanoylphorbol-13-acetate (TPA) induces DOC-2/DAB2 phosphorylation, including a serine residue at position 24. Mutation of Ser24 to Ala reduced DOC-2/DAB2 phosphorylation by PKC. Using a synthetic Ser24 peptide (APS24KKEKKKGSEKTD) or recombinant DOC-2/DAB2 as substrates, PKCβII, PKCγ, and PKCδ (but not casein kinase II) directly phosphorylated Ser24 in vitro. This indicates that DOC-2/DAB2 is a PKC-specific substrate. Since expression of wild-type DOC-2/DAB2, but not the S24A mutant, inhibited TPA- induced AP-1 activity in prostatic epithelial cells, phosphorylation of Ser24 appears to play a critical role in modulating TPA-induced AP-1 activity. Taken together, these data suggest that PKC-regulated phosphorylation of DOC-2/DAB2 protein may help its growth inhibitory function.
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U2 - 10.1074/jbc.274.45.31981
DO - 10.1074/jbc.274.45.31981
M3 - Article
C2 - 10542228
AN - SCOPUS:0033527544
SN - 0021-9258
VL - 274
SP - 31981
EP - 31986
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 45
ER -