AR and post translational modifications

Despite the AR's role in genomic upregulation of androgen dependent gene transcription, its activation can signal through alternative means at the plasma membrane and cytoplasm (referred to as non-genomic signaling) [1]. For example, the AR can trigger intracellular calcium release and the activation of protein kinases such as the Mitogen Activated Protein Kinases (MAPK), Protein Kinase A (PKA), AKT and PKC [7]. Phosphorylation of the AR by MAPK, JNK, AKT, ERK, p38, increases AR response to low level of androgens, estrogens, and anti-androgens as well as enhances the recruitment of co-activators [7]. Furthermore, the AR itself is a downstream substrate for phosphorylation by receptor-tyrosine kinases and G-protein coupled receptor signaling. The phosphorylation of AR is mediated by the recruitment of kinases in the presence or absence of androgens. Phosphorylation at Serine (Ser) residues, Ser80, Ser93, and Ser641 is thought to protect the AR from proteolytic degradation [7, 48]. Alternatively, AR degradation is regulated by the phosphorylation of specific residues recognized by E3 ubiquitin ligase. For example, MDM2 E3 ubiquitin ligase promotes polyu-biquitylation of the AR by recognizing AKT dependent phosphorylated serine [3,49]. Moreover, transactivation of the AR largely relies upon the phosphorylation of Ser213, Ser506, and Ser650 [7]. Phosphorylation of the AR is required for its effects within the nucleus and the AR should remain hyperphosphorylated to mediate its transcriptional role [3]. Studies have also shown constitutive phosphorylation of the AR at Ser94 as well as on other serine residues such as Ser16, 81, 256, 309, and 424. The loss of phosphorylation results in the loss of transcriptional activity and nuclear localization [3, 50-52]. Specifically, Yang et al., (2005) demonstrated that dephosphorylation of AR at the NTD by protein phosphatase 2A (PP2A), resulted in the loss of AR activity.

The AR receptors can also be acetylated, and sumoylated. These types of post translational modifications have also been shown to affect receptor stability and activity. The KXKK motif of the hinge region is a site for acetylation. Mutations of lysine to alanine reduced the tran-scriptional activity of AR by favoring NCoR interactions [3, 53]. Sumoylation of the AR is hormone dependent and competes with ubiquitination of lysine residues. Sumoylation is thought to repress AR activity. Disruption of sumoylation on Lys386 and Lys520 resulted in an increase in AR transactivation [3, 54].

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