Androgen receptor nucleocytoplasmic trafficking - A one-way journey

Abstract

The androgen receptor (AR) is a key regulator of the growth and proliferation of prostate cancer. The majority of lethal castration-resistant prostate cancer (CRPC) growth is still dependent on AR activity. The AR need to be in the nucleus to exert its biological action as a transcription factor. As such, defining the mechanisms that regulate the subcellular localization of AR are important. Previously it was believed that AR was imported into the nucleus in a ligand-dependent manner and subsequently exported out of the nucleus upon ligand withdrawal. Recent evidence has challenged this decades-old paradigm and showed that the AR is degraded, not exported, in the nucleus. This review discusses the current understanding of how AR nucleocytoplasmic localization is regulated by import and through nuclear degradation.

Figure 1.

The structure of the androgen receptor (AR) and major regions influencing AR localization. The androgen receptor contains an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (H), and a ligand-binding domain (LBD). Nuclear import is regulated by the nuclear localization signal 1 (NLS1) and nuclear localization signal 2 (NLS2). Due to the NLS2 only being active in the liganded AR, the exact amino acid region of the NLS2 is undefined. The nuclear degradation signal (NDS) promotes the nuclear specific degradation of unliganded AR.

Figure 2:

The classical and updated models of AR nucleocytoplasmic trafficking. In the classical model, the import of AR is androgen-dependent and the AR functions as a transcription factor in the nucleus upon nuclear import. Upon androgen withdrawal, androgen dissociates from the AR, which causes the AR to be exported out of the nucleus. Additional evidence and reconsideration of existing evidence led to the updated model. In the updated model, import can also be androgen-independent and the AR is degraded in the nucleus, not exported, following androgen withdrawal.

Figure 3:

Primary structure of the nuclear degradation signal in the androgen receptor (AR), mineralocorticoid receptor (MR), estrogen receptor (ER), progesterone receptor (PR), and glucocorticoid receptor (GR). ClustalW analysis shows the sequence homology between the different receptors. The five receptors all have a similar secondary structure containing a β-turn (blue) and helices 5–8 (yellow) of the ligand binding domain. The nuclear degradation properties of this region have been experimentally validated in the AR, MR, and ER (Saporita et al., 2003).

Figure 4:

Three-dimensional structure of the AR ligand binding domain (LBD) with ligand R1881 (Matias, Donner, Coelho et al., 2000). The nuclear degradation signal (NDS) highlighted in blue is in close proximity to the binding of ligand R1881 (green). The position of L859 is highlighted in pink; its mutation to F prevents androgen binding to the LBD. The structure of unliganded LBD is not known, so the structure of the active NDS in unliganded AR is unclear.