Impact of phosphorylation on androgen receptor biology and pathology

Androgen receptor (AR) is the transcription factor mediating the effects of androgens at genetic level. Like other nuclear receptors, it is organized in 3 main domains: the large N-terminal domain, disordered and with important regulatory functions, the well-structured DNA binding domain and the well characterised Ligand Binding Domain. It is linked to several pathological conditions: while the loss of function of the protein causes androgen insensitivity syndrome, the gain of function is triggering prostate cancer. In the case of expansion of a poly-glutamine stretch in the N-terminal domain, adult males develop Spinal and Bulbar Muscular Atrophy (SBMA).
AR is a heavily phosphorylated. One phosphorylation site is constitutive while the others are phosphorylated in response to androgens or other stimuli. Phosphorylation is able to tune, abolish or boost the activity of AR and it is also dysregulated in pathologies like cancer and SBMA. The project aims to characterize the effects of phosphorylation on AR at molecular level, using integrated structural, cell biology and omics approaches. The long terms objectives aim to contribute to the knowledge of AR basic biology and ways to find therapeutic strategies for AR linked diseases

Members:
Laura Tosatto (Principal investigator)