Controlling PTEN (Phosphatase and Tensin Homolog) Stability

Abstract

Phosphatase and tensin homolog (PTEN) is a phosphoinositide lipid phosphatase and one of the most frequently disrupted tumor suppressors in many forms of cancer, with even small reductions in the expression levels of PTEN promoting cancer development. Although the post-translational ubiquitination of PTEN can control its stability, activity, and localization, a detailed understanding of how PTEN ubiquitination integrates with other cellular regulatory processes and may be dysregulated in cancer has been hampered by a poor understanding of the significance of ubiquitination at individual sites. The function of the phosphatase and tensin homolog (PTEN) 3 tumor suppressor is disrupted in many forms of cancer by diverse mechanisms (1, 2). PTEN is a phosphatidylinositol 3,4,5-trisphosphate lipid phosphatase that acts to oppose the class I phosphoinositide 3-kinases and therefore loss of PTEN function leads to aberrant accumulation of phosphatidylinositol 3,4,5-trisphosphate and activation of downstream oncogenic PI3K-dependent signaling as well as potentially other PI3K-independent changes (2, 3). PTEN is currently known to exist in two forms, a 403-amino acid cytosolic and nuclear protein usually simply called PTEN, and a longer 576-amino acid protein, PTEN-L, which due to its ability to cross cell membranes and inhibit tumor formation when injected into in mice, has been proposed as a protein therapy (4 -6).Although in clinical data from some tumor types, notably breast cancer, reduced PTEN mRNA levels correlate well with reduced PTEN protein (7), in others including prostate cancer, reduced PTEN protein levels are frequently observed in tumors apparently retaining normal levels of PTEN mRNA (8). Among the mechanisms potentially responsible for this selective loss of PTEN protein expression, accelerated degradation by posttranslational ubiquitination seems likely to contribute. This conclusion is supported by the paradigm established for the p53 protein and the ubiquitin E3 ligase MDM2 that destabilization of tumor suppressor proteins can be a significant oncogenic driver and also accumulating evidence for the dysregulation of ubiquitin ligases and proteases that control PTEN stability in several cancer types (9 -12).In addition to its stability, the activity and localization of PTEN can also be controlled by its ubiquitination, notably with PTEN monoubiquitination being linked to its nuclear accumulation (13-15). Several E3 ubiquitin ligases have been proposed to contribute to PTEN ubiquitination, including NEDD4 and the related HECT-domain E3 ligase WWP2, as well as XIAP, CHIP, RFP, SPOP, and MKRN1 (9, 10, 16 -20) and ubiquitin proteases have been identified that can deubiquitinate PTEN, including HAUSP/USP7, OTUD3, and USP13 (11,12,21). Although many of these studies have identified important effects of manipulating these ligases and proteases on PTEN function and often PTEN stability, clear pictures are yet to emerge of the molecular details of these regulatory events, in particular the sites at which PTEN be...

The functions of tumor suppressor PTEN in innate and adaptive immunity

“…There are at least five lysine residues that may be ubiquitinated: Lys13, Lys48, Lys66, Lys80 and Lys289. 41 Monoubiquitination can influence the accumulation of PTEN in the nucleus. Polyubiquitination of PTEN leads to its degradation by the proteasome complex.…”

Analysis of the FLVR motif of SHIP1 and its importance for the protein stability of SH2 containing signaling proteins

“…It has previously been shown for PTEN that lysine at position 66 also exerts an influence on regulation of its expression status. Accordingly, the de-ubiquitination mutant K66R led to an increased expression of PTEN and a concomitant reduction in the phosphorylation of AKT S473 and T308 (Gupta and Leslie, 2016). Due to the lack of endogenous expression of PTEN in H1299 cells, the expression of SHIP1 has a direct influence on the phosphorylation of AKT-S473 and moreover on viability and growth of the cells.…”

Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition

“…Among the PI3K/AKT axis, phosphatase and tensin homolog (PTEN) plays a key catalytic role in the conversion of the phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) to PIP 2 , by which negatively regulates AKT signaling activation [8]. The catalytic activity of PTEN protein is dependent on phosphorylation at the PTEN C2 domain, including Ser-380, Thr-382, Thr-383, and Ser-385 [9,10], whereas PTEN stability is controlled by ubiquitination at residues Lys-13, Lys-27, Lys-66, and Lys-289 [11][12][13]. Recent studies indicate that PTEN not only regulates DNA repair through the AKT/p38 signaling axis in the cytoplasm [14] but also translocates into the nucleus to confer chromosome stability against DNA damage by modulating p53 activity and inhibiting nuclear AKT activation [15,16].…”