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

Ching Ping Tseng, Brent D. Ely, Rey Chen Pong, Zhi Wang, Jian Zhou, Jer Tsong Hsieh

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)31981-31986
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number45
DOIs
StatePublished - Nov 5 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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