Suppression of androgen receptor transactivation by Pyk2 via interaction and phosphorylation of the ARA55 coregulator.
The proline-rich tyrosine kinase 2 (Pyk2) was first identified as a key kinase linked to the MAP kinase and JNK signaling pathways that play important roles in cell growth and adhesion. The linkage between Pyk2 and the androgen receptor (AR), an important transcription factor in prostate cancer progression, however, remains unclear. Here we report that using the full-length androgen receptor-associated protein, ARA55, coregulator as bait, we were able to isolate an ARA55-interacting protein, Pyk2, and demonstrated that Pyk2 could repress AR transactivation via inactivation of ARA55. This inactivation may result from the direct phosphorylation of ARA55 by Pyk2 at tyrosine 43, impairing the coactivator activity of ARA55 and/or sequestering ARA55 to reduce its interaction with AR. Our finding that Pyk2 can indirectly modulate AR function via interaction and/or phosphorylation of ARA55 not only expands the role of Pyk2 in AR-mediated prostate cancer growth but also strengthens the role of ARA55 as an AR coregulator.
Wang
Xin
X
George Whipple Laboratory for Cancer Research, Department of Urology and the Cancer Center, University of Rochester, Rochester, New York 14642, USA.
Yang
Yue
Y
Guo
Xiaojian
X
Sampson
Erik R
ER
Hsu
Cheng-Lung
CL
Tsai
Meng-Yin
MY
Yeh
Shuyuan
S
Wu
Guan
G
Guo
Yinglu
Y
Chang
Chawnshang
C
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D051418:Focal Adhesion Kinase 2; D015723:Gene Library; D017930:Genes, Reporter; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008297:Male; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011467:Prostate / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; C490351:TGFB1I1 protein, human; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2