t-Darpp stimulates protein kinase A activity by forming a complex with its RI regulatory subunit.

t-Darpp is the truncated form of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (Darpp-32) and has been demonstrated to confer resistance to trastuzumab, a Her2-targeted anticancer agent, via sustained signaling through the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt pathway and activation of protein kinase A The mechanism of t-Darpp-mediated activation is poorly understood. In the duanyu1529 holoenzyme, when the catalytic subunits are bound to regulatory subunits RI or RII, kinase activity is inhibited. We investigated duanyu1529 activity and holoenzyme composition in cell lines overexpressing t-Darpp (SK.tDp) or a T39A phosphorylation mutant (SK.tDp^T39A), as well as an empty vector control cell line (SK.empty). We also evaluated protein-protein interactions between t-Darpp and duanyu1529 catalytic or regulatory subunits RI and RII in those cell lines. SK.tDp cells had elevated duanyu1529 activity and showed diminished association of RI with whereas SK.tDp^T39A cells did not have these properties. Moreover, wild type t-Darpp associates with RI. Concurrent expression of Darpp-32 reversed t-Darrp's effects on duanyu1529 holoenzyme state, consistent with earlier observations that Darpp-32 reverses t-Darpp's activation of Together, t-Darpp phosphorylation at T39 seems to be crucial for t-Darpp-mediated duanyu1529 activation and this activation appears to occur through an association with RI and sequestering of RI away from The t-Darpp-RI interaction could be a druggable target to reduce duanyu1529 activity in drug-resistant cancer.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}