PTEN proteoforms in biology and disease

Abstract

Proteoforms are specific molecular forms of protein products arising from a single gene that possess different structures and different functions. Therefore, a single gene can produce a large repertoire of proteoforms by means of allelic variations (mutations, indels, SNPs), alternative splicing and other pre-translational mechanisms, post-translational modifications (PTMs), conformational dynamics, and functioning. Resulting proteoforms that have different sizes, alternative splicing patterns, sets of post-translational modifications, protein-protein interactions, and protein-ligand interactions, might dramatically increase the functionality of the encoded protein. Herein, we have interrogated the tumor suppressor PTEN for its proteoforms and find that this protein exists in multiple forms with distinct functions and sub-cellular localizations. Furthermore, the levels of each PTEN proteoform in a given cell may affect its biological function. Indeed, the paradigm of the continuum model of tumor suppression by PTEN can be better explained by the presence of a continuum of PTEN proteoforms, diversity, and levels of which are associated with pathological outcomes than simply by the different roles of mutations in the PTEN gene. Consequently, understanding the mechanisms underlying the dysregulation of PTEN proteoforms by several genomic and non-genomic mechanisms in cancer and other diseases is imperative. We have identified different PTEN proteoforms, which control various aspects of cellular function and grouped them into three categories of intrinsic, function-induced, and inducible proteoforms. A special emphasis is given to the inducible PTEN proteoforms that are produced due to alternative translational initiation. The novel finding that PTEN forms dimers with biological implications supports the notion that PTEN proteoform-proteoform interactions may play hitherto unknown roles in cellular homeostasis and in pathogenic settings, including cancer. These PTEN proteoforms with unique properties and functionalities offer potential novel therapeutic opportunities in the treatment of various cancers and other diseases.

Expression of Human PTEN-L in a Yeast Heterologous Model Unveils Specific N-Terminal Motifs Controlling PTEN-L Subcellular Localization and Function

“…Thus, either translocation or retention of GFP-PTEN-L* into the yeast nucleus seems dependent of the presence this poly-Arg stretch. This result is in consonance with evidence reported by Liang et al, who found that the mutation of this sequence eliminated PTEN-M nucleolar localization [38], and with the in-silico prediction of the PTEN-L R6 motif as a nuclear localization sequence [48]. Figure 5C).…”

PTEN Physically Interacts with and Regulates E2F1-mediated Transcription in Lung Cancer

“…Although the exact mechanism of this loss of function is not clear, it is possible that these PTEN mutants have altered nuclear localization patterns, or have impaired E2F1 binding capabilities, which remains to be elucidated. The recent findings of PTEN dimerization [70] and existence of multiple PTEN proteoforms [71] supports the notion that the PTEN mutations in the C2 domain may engage in aberrant PTEN homo/hetero-dimerization, leading to loss of PTEN function. In summary, our transcriptional studies indicate that both PTEN-WT and PTEN-4A can inhibit the transcription of E2F1 regulated genes and that the tumor suppressive effect of PTEN-4A is more pronounced due to its enhanced lipid-phosphatase activity, increased nuclear localization and accessibility of the C2 domain.…”

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

“…Reduced PTEN expression leads to PIP3 accumulation resulting in activation of PI3kinase followed by phosphorylation of AKT. AKT is a pro-cell survival protein that is well documented for its role in HSC proliferation and migration [13,46]. A recent report suggests that PTEN overexpression by adenovirus in the CCl 4 -induced rat liver fibrosis model reduced serum ALT and AST while decreasing collagen deposition in the liver [47].…”

“…The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a dual phosphatase, and its major function is to dephosphorylate phosphatidylinositol 3, 4, 5‑triphosphate (PIP3) to phosphatidylinositol 4, 5‑bisphosphate [13]. Decreased PTEN expression has been reported in fibrotic diseases of the lungs, heart, skin as well as liver [14–18].…”