PTEN is a critical tumour suppressor that is frequently mutated in human cancer. 
We have previously identified a CUG initiated PTEN isoform designated PTENα, 
which functions in mitochondrial bioenergetics. Here we report the 
identification of another N-terminal extended PTEN isoform, designated PTENβ. 
PTENβ translation is initiated from an AUU codon upstream of and in-frame with 
the AUG initiation sequence for canonical PTEN. We show that the Kozak context 
and a downstream hairpin structure are critical for this alternative initiation. 
PTENβ localizes predominantly in the nucleolus, and physically associates with 
and dephosphorylates nucleolin, which is a multifunctional nucleolar 
phosphoprotein. Disruption of PTENβ alters rDNA transcription and promotes 
ribosomal biogenesis, and this effect can be reversed by re-introduction of 
PTENβ. Our data show that PTENβ regulates pre-rRNA synthesis and cellular 
proliferation. These results demonstrate the complexity of the PTEN protein 
family and the diversity of its functions.