The nuclear affairs of PTEN

Abstract

PTEN encodes a major tumor-suppressor protein that is a dual-specificity phosphatase. Inactivation of PTEN has been shown to be involved in heritable and sporadic cancers. Mutation or deletion of PTEN, historically the most commonly identified mechanisms of inactivation of tumor suppressors, is found only in the minority of sporadic non-cultured primary cancers, which indicates that there might be other, novel mechanisms of inactivation. Despite the absence of a classic nuclear localization signal, PTEN enters the nucleus by several mechanisms, including simple diffusion, active shuttling, cytoplasmic-localization-signal-dependent export and monoubiquitylation-dependent import. Cytoplasmic PTEN has a well-known role as a negative regulator of the PI3K/AKT pathway; however, it is becoming clear that cytosolic PTEN is not the same as nuclear PTEN. Nuclear PTEN plays a role in chromosome stability, DNA repair, cell cycle arrest and cellular stability. The balance between these functions is an important factor in determining whether a cell remains benign or becomes neoplastic.

Multiple forms of PKR present in the nuclei of acute leukemia cells represent an active kinase that is responsive to stress

“…35 Loss of PTEN is associated with enhanced phosphatidylinositol-3,4,5-phosphate levels and constitutive activation of the AKT-mTOR pathway. Much of the PTEN in the cell is located in the nucleus, wherein it controls nuclear and chromosomal integrity.…”

“…Much of the PTEN in the cell is located in the nucleus, wherein it controls nuclear and chromosomal integrity. 35 Through its PDZ domain, PTEN represses Bmi-1 activity in the nucleus. 36 Bmi-1 functions indirectly to suppress the expression of p14 Arf , a cell cycle regulator responsible for the displacement of PKR from nucleophosmin and subsequent redistribution of active PKR.…”

Post-translational regulation of PTEN

“…Furthermore, because the majority of PTEN protein is cytosolic and PTEN nuclear translocation is enhanced under specific conditions, PTEN nuclear translocation and, thus, the function of nuclear PTEN have to be regulated. Besides ubiquitination, there are multiple other possible mechanisms that have been proposed to control PTEN nuclear localization (Chung et al, 2005;Minaguchi et al, 2006;Planchon et al, 2008).…”

p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN

“…3 Although PTEN was initially identified as a cytoplasmic protein, 4,5 PTEN nuclear localization has since been reported in many normal and tumor cell types. 6 Interestingly, nuclear PTEN, like cytoplasmic PTEN, may also exert tumor suppressor activity. Numerous studies have reported that many components of the PI3K signaling pathway, including phosphatidylinositol 4,5-bisphosphate (PIP 2 ), PIP 3 , PI3K, and AKT2, are present in nuclei.…”