1. ¹Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
2. ²Division of Pediatric Hematology and Oncology, Department of Pediatrics, AFLAC Cancer Center and Blood Disorder Service, Emory School of Medicine, Atlanta, GA, USA

Correspondence: Dr G Denning, Department of Pediatrics, The Winship Cancer Center, Emory School of Medicine, 1365 Clifton Road, Bldg. C, Room 5054D, Atlanta, GA 30322, USA. E-mail: gabriela_denning@oz.ped.emory.edu

³Current address: Division of Pediatric Hematology and Oncology, Department of Pediatrics, AFLAC Cancer Center and Blood Disorder Service, Emory School of Medicine, Atlanta, GA, USA.

⁴These authors have contributed equally to this work.

Received 27 January 2006; Revised 10 February 2006; Accepted 10 February 2006; Published online 8 January 2007.

Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an important negative regulator of cell growth and a tumor suppressor. Its growth-attenuating activity is based on the dephosphorylation of phosphatidylinositol 3,4,5-trisphosphate (PIP₃), an essential second messenger for the phosphoinositide 3-kinase/Akt signaling pathway. This activity may require localization of PTEN to cytoplasmic membranes. Yet PTEN can also localize to the cell nucleus where its functions remain unclear. Here we present data that define a short sequence in the N-terminal region of PTEN required for cytoplasmic localization. We will refer to this sequence as cytoplasmic localization signal (CLS). It could function as a non-canonical signal for nuclear export or as a cytoplasmic retention signal of PTEN. Mutations within the CLS induce nuclear localization and impair growth suppressive activities of PTEN while preserving lipid phosphatase activity. We propose that nuclear localization of PTEN is not compatible with plasma membrane-targeted growth suppressive functions of PTEN.