Receptor for Activated C Kinase 1 (RACK1) and Src Regulate the Tyrosine Phosphorylation and Function of the Androgen Receptor

Abstract

The androgen receptor (AR) remains functionally important in the development and progression of prostate cancer even when the disease seems androgen ''independent.'' Because signal transduction by growth factor receptors increases in advanced prostate cancer and is capable of sensitizing the AR to androgen, there is considerable interest in determining the mechanisms by which signaling systems can modulate AR function. We show herein that the adaptor/scaffolding protein receptor for activated C kinase 1 (RACK1), which was previously reported to interact with the AR, modulates the tyrosine phosphorylation of AR and its interaction with the Src tyrosine kinase. We also show that down-regulation of RACK1 by short interfering RNA inhibits growth and stimulates prostate-specific antigen transcription in androgentreated prostate cancer cells. Our results suggest that RACK1 mediates the cross-talk of AR with additional binding partners, such as Src, and facilitates the tyrosine phosphorylation and transcriptional activity of the AR. (Cancer Res 2006; 66(22): 11047-54)

Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation

“…While this manuscript was in preparation, two groups reported AR phosphorylation at Tyr-534 by Src tyrosine kinase (17,23). Although several kinases may be capable of phosphorylating AR, our data demonstrate that Tyr-534 is not involved in Ack1-dependent AR transactivation.…”

Regulation of the androgen receptor by post-translational modifications

“…Using mass spectrometry, p-Tyr534 was identified (Guo et al 2006) and subsequently verified (Kraus et al 2006). Interestingly, AR mutations at this site cannot be activated by EGF but they can still be activated by DHT, although are unresponsive to lower DHT concentrations.…”

“…Furthermore, Tyr534-mutant AR is not stimulated to translocate to the nucleus by Src activation (Guo et al 2006). The scaffold protein GNB2L1 (RACK1), which interacts with the AR to facilitate ligand-independent AR nuclear translocation (Rigas et al 2003), can also modulate AR tyrosine phosphorylation and its interaction with Src (Kraus et al 2006). Tyr534 phosphorylation is increased in refractory xenograft models and is present in refractory human samples of PC.…”

Molecular genetics of prostate cancer: new prospects for old challenges

“…In prostate cancer, aberrant tyrosine kinase signaling, particularly through Her2/ Neu or SRC tyrosine kinases, has been implicated in aggressive disease, progression to metastasis, and castration resistance, and, consequently, has been implicated as a key therapeutic target in patients with advanced disease (Mellinghoff et al 2004;Fizazi 2007). In particular, stimulation of AR signaling leads to activation of SRC in prostate cancer cells, which can lead to phosphorylation of AR, castration resistance, and cellular proliferation and invasiveness (Migliaccio et al 2000;Agoulnik et al 2005;Kraus et al 2006). However, most functional analyses of SRC and other oncogenic tyrosine kinases have been limited to studies of prostate cancer cell lines in culture or in xenografts, and further insights will require analyses of in vivo models and correlative studies of clinical specimens.…”