PTEN/PTENP1: 'Regulating the regulator of RTK-dependent PI3K/Akt signalling', new targets for cancer therapy

Abstract

Regulation of the PI-3 kinase (PI3K)/Akt signalling pathway is essential for maintaining the integrity of fundamental cellular processes, cell growth, survival, death and metabolism, and dysregulation of this pathway is implicated in the development and progression of cancers. Receptor tyrosine kinases (RTKs) are major upstream regulators of PI3K/Akt signalling. The phosphatase and tensin homologue (PTEN), a well characterised tumour suppressor, is a prime antagonist of PI3K and therefore a negative regulator of this pathway. Loss or inactivation of PTEN, which occurs in many tumour types, leads to overactivation of RTK/PI3K/Akt signalling driving tumourigenesis. Cellular PTEN levels are tightly regulated by a number of transcriptional, post-transcriptional and post-translational regulatory mechanisms. Of particular interest, transcription of the PTEN pseudogene, PTENP1, produces sense and antisense transcripts that exhibit post-transcriptional and transcriptional modulation of PTEN expression respectively. These additional levels of regulatory complexity governing PTEN expression add to the overall intricacies of the regulation of RTK/PI-3 K/Akt signalling. This review will discuss the regulation of oncogenic PI3K signalling by PTEN (the regulator) with a focus on the modulatory effects of the sense and antisense transcripts of PTENP1 on PTEN expression, and will further explore the potential for new therapeutic opportunities in cancer treatment.

Keywords: Cancer; PI-3 kinase (PI3K); PTENP1; Phosphatase and tensin homologue (PTEN); Pseudogene; Tyrosine kinase; microRNA (miRNA).

Fig. 1

PTEN protein structure and sites of post-translational modification. PTEN is composed of 403 amino acids and is characterised by five functional domains: a phosphatidylinositol-4,5-bisphosphate (PIP2)-binding domain (PBD), a phosphatase domain containing the catalytic core, a C2 domain with putative ubiquitination sites, two PEST (proline, glutamic acid, serine, threonine) domains for degradation, and a PDZ interaction motif for protein-protein interactions. Post-translational regulation of PTEN occurs by ubiquitination (Ub) of Lys residues within the PBD and C2 domain, by oxidation, SUMOylation within the C2 domain, and acetylation on protein tyrosine phosphatase (PTPase) and PDZ-binding sites. Furthermore, PTEN is regulated by phosphorylation of specific serine and threonine residues within the C2 domain and C-tail terminal of PTEN (Modified from [14, 15])

Fig. 2

Pseudogene types shown to occur in the human genome. a Unitary pseudogenes are once functional gene sequences that have lost gene function due to the accumulation of mutations over time. b Non-processed pseudogenes are the result of direct duplication of existing genes, after which the duplicated version becomes inactivated due to the accumulation of mutations in sequences essential for gene expression. c Processed pseudogenes are the result of retrotransposition events. In this case, the mature mRNA transcript of a gene is reverse transcribed into a cDNA copy, which is then integrated into the genome of the organism. The site of integration of pseudogenes is random (Adapted from [61])

Fig. 3

Regulation of PTEN by the sense and antisense transcripts of its processed pseudogene PTENP1: regulating the regulator of PI3K signalling. PTENP1 is transcribed into a sense and 2 antisense transcripts (a and b). In the cytoplasm, the sense transcript (PTENP1(S)) acts as competing endogenous RNA, competing with PTEN for the binding of PTEN-targeting miRNAs and thus freeing PTEN from miRNA-mediated repression and increasing PTEN cellular abundance. Of the 2 antisense PTENP1 transcripts, PTENP1(AS)α and PTENP1(AS)β produced, PTENP1(AS)α acts in the nucleus to negatively regulate PTEN transcription by recruiting chromatin-repressor proteins, the Enhancer of Zeste Homolog 2 and DNA methyltransferase 3a (EZH2) and DNA methyltransferase 3a (DNMT3a) to the PTEN promoter. Conversely, also in the cytoplasm, PTENP1(AS)β acts to stabilise the PTENP1(S) transcript through RNA-RNA interactions, as this the sense transcript lacks a poly(A) tail, and hence reinforces the miRNA ‘sponging’ activity of PTENP1(S) (modified from [42])

Fig. 4

Regulation of PTEN, a major regulator of the PI3K/AKT signalling pathway. Growth factors bind receptor tyrosine kinases (RTKs) on the extracellular cell membrane, which leads to the recruitment and binding of PI3K (directly or through adaptor proteins) to its cytoplasmic domain through its regulatory subunit (P85). Activated PI3K phosphorylates of PI(4,5)P2 to PI(3,4,5)P3, which occurs through its catalytic subunit (P110). The serine/threonine kinases Akt and PDK1 are recruited to the membrane after binding to the pleckstrin homology (PH) domain of PI(3,4,5)P3. PDK1 and mTORC2 phosphorylate and activate Akt, which phosphorylates a number of downstream protein targets with the overall effect of enhancing cell proliferation, metabolism and survival whilst inhibiting apoptosis. PTEN is a major negative regulator of PI3K/Akt signalling through its phosphoinositide phosphatase activity which acts to directly antagonise Pi3K activity by dephosphorylating PI(3,4,5)P3 to PI(4,5)P2. PTEN abundance and activity is highly regulated through various complementary mechanisms working at the transcriptional, post-transcriptional and post-translational levels (modified from [14])