Darpp-32 and Its Truncated Variant t-Darpp Have Antagonistic Effects on Breast Cancer Cell Growth and Herceptin Resistance

Several intracellular changes, including down-regulation of PKA-RIIα, PKIγ and PTG (green arrows) and up-regulation of t-Darpp (red arrow) work coordinately to enhance PKA activity. PKA, in turn, either activates the PI3K/Akt pathway (possibly through EGFR or the p85 regulatory subunit of PI3K) or promotes sustained phospho-Akt levels by activating the PP-1 inhibitory activity of Darpp-32. This activity is stimulated via a phosphorylation event at Thr-34, which is absent from t-Darpp. A second phosphorylation event, at Thr-75, activates Darpp-32 as a PKA inhibitor. We speculate that t-Darpp may interfere with this PKA inhibition via a dominant negative mechanism. Dashed lines indicate activities that are down-regulated in BT/HerR cells relative to BT474 cells. Question marks indicate hypothetical pathways that are activated in BT/HerR cells. All other pathways represent well established activities associated with the indicated proteins and enzymes. Abbreviations not already cited: PDK1/2, 3-phosphoinositide-dependent kinase-1/2; Pten, phosphatase and tensin homologue deleted in chromosome 10; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate.

Publication

Darpp-32 and Its Truncated Variant t-Darpp Have Antagonistic Effects on Breast Cancer Cell Growth and Herceptin Resistance. (2009) Long Gu, et al. PLoS One. 2009;4(7):e6220. Figure: F5. All organisms Drosophila melanogaster Homo sapiens

Disease mentions