PI3K/Akt Signaling and Androgen Receptor Phosphorylation
The androgen receptor (AR) is an ~110 kDa androgen-dependent transcription factor that is a member of the steroid/nuclear receptor gene superfamily. The AR signaling pathway plays a key role in the development and function of male reproductive organs, including the prostate and epididymis. AR also plays a role in non-reproductive organs, such as muscle, hair follicles, and brain. Abnormalities in the AR signaling pathway have been linked to a number of diseases, including prostate cancer, male infertility and Kennedy's disease (spinal bulbar muscular atrophy). Kennedy's disease is an incurable X-linked recessive genetic progressive neuro-muscular disease.
The PI3K/Akt signaling pathway plays an integral role in regulating AR activity through phosphorylation of AR at Ser213/210 and Ser791/790. Phosphorylation of AR through the PI3K/Akt pathway is induced by both growth factors and cytokines. For example, IGF-1 activates the phosphatidylinositol 3-kinase(PI3K)/AKT pathway in prostate cancer LNCap cells at high passage number and increases phosphorylation of of AR at Ser213/210 (see western blot with IMG-561) and Ser791/790 (Lin et al. 2003). The western blot results also show that inhibition of the PI3K/Akt pathway by LY294002 prior to incubation with IGF-1 suppressed AR phosphorylation at Ser231/210.
Phosphorylated AR, like many other phosphorylated proteins, is ubiquitinatedand targeted for protein degradation. Phosphorylation of AR at Ser213/210 and Ser791/790 by the PI3K/Akt signaling pathway can play an essential role in the hormone independent activation of the androgen receptor. AR phosphorylation is thought to have a survival role in prostate cancer by protecting cells from apoptosis, and thereby promoting cell survival.
Product Citations 1. Suppression Versus Induction of Androgen Receptor Functions by the Phosphatidylinositol 3-Kinase/Akt Pathway in Prostate Cancer LNCaP Cells with Different Passage Numbers. Lin, H-K., Y-C Hu, L. Yang, S. Altuwaijri. 2003. J. Biol. Chem. 278: 50902-50907
LNCaP cells (passage number 38) were serum-starved for 2 days. After serum starvation, cells were (A) left untreated, (B) treated with 100 ug/ml IGF-1 for 4h, or (C) incubated with 20 um LY294002 for 30 min prior to treatment with 100 ug/ml IGF-1 for 4 hours.
Staining of 35µg of Human Brain lysate using IMG-3238 at 0.3µg/ ml. Primary incubation was 1 hour. Detected by chemiluminescence.
Western blot analysis of ubiquitin using IMG-5021 in human (Daudi, HL60. HeLa, and Jurkat) and mouse (Raw) cell lines. Ubiquitin migrates at ~8 kDa. Higher bands observed in Daudi, HL60 and Jurkat correspond to various ubiquitinated proteins.
