The PTEN gene is a tumor suppressor gene that is widely changed and closely related to tumorigenesis. This gene encodes the classic PTEN protein consisting of 403 amino acids. PTEN protein has phosphatase activity, which can inhibit the occurrence and development of tumors by antagonizing the activity of phosphorylases such as tyrosine kinase. PTEN proteins can enter the nucleus through multiple mechanisms. Nuclear PTEN can interact with a variety of proteins, affect the stability of the genome, etc., and exert a tumor-suppressive effect.

The main substrate of PTEN is a component of the lipid membrane PIP3, which inhibits the activation of the proto-oncogene PI3K-AKT-mTOR signaling pathway $$$ through PIP3. PTEN has phosphatase activity on peptides phosphorylated on Tyr, Ser, and Thr in vitro, making it a bispecific protein phosphatase, which belongs to both protein tyrosine phosphatase and non-phosphatase-dependent functions.

PTEN plays a tumor-suppressive role as a scaffold protein in the nucleus and cytoplasm. In a mouse model, PTEN can be independent of the PI3K-AKT signaling pathway, and its loss is different from AKT overexpression. In the nucleus, PTEN regulates various processes, such as cell proliferation, transcription, and maintaining genome stability. In the cytoplasm, PTEN regulates the activity of IP3R, which in turn regulates Ca-mediated apoptosis.

The physiological function of PTEN

From the above, PTEN plays a key role in various biological processes through PIP3-dependent and PIP3-independent pathways.

PTEN protein deficiency activates the PI3K-AKT-mTORC1 pathway, drives metabolic reprogramming of tumor cells, and allows tumor cells to rapidly proliferate and grow. Since insulin-mediated metabolic responses are mainly achieved through PI3K, PTEN also plays a key role in regulating insulin-induced glucose uptake.

After PTEN activation, PIP3 is adjusted to help establish a PIP3-PIP2 gradient and thus regulate cell motility and polarity. In addition, PTEN can inhibit cell migration through its C2 domain and protein phosphatase activity. Cell migration is an important process in embryogenesis, morphogenesis, angiogenesis, immune response and metastasis. The inactivation of PTEN may lead to the loss of basal polarity and tight junctions, leading to the loss of epithelial polarization and increased cell migration, and promote tumor cell invasion.

PTEN maintains centromere stability by interacting with CENPC, and also actively repairs DNA damage by inducing the DNA repair protein RAD51, and ubiquitin-like nuclear PTEN also controls DNA damage repair. Therefore, PTEN-deficient cells have abnormal DNA damage sensitive.

PTEN mainly regulates cell proliferation by inducing cell cycle arrest through the PI3K-AKT pathway. It can also downregulate cyclin D1 activity by transcription or restrict its accumulation in the nucleus. Nuclear PTEN can form a complex with histone acetyltransferase p300, which is required for PTEN-mediated cell cycle arrest. The formation of this complex maintains high levels of p53 acetylation and regulates p53 stability and transcription active.

PTEN expression is subject to a variety of transcriptional and post-transcriptional regulatory mechanisms, such as gene deletion, mutation, apparent silencing, and transcriptional repression. In addition, PTEN is subject to a number of other specific regulatory mechanisms, including PTMs, PTEN-interacting proteins, dimeric forms, and secretion.

In summary, PTEN plays an important role in cells, from inhibiting cell growth, proliferation, and migration to promoting apoptosis, DNA damage repair, and inhibiting tumor metabolism. PTEN also plays PI3K-AKT independence and protein in the nucleus. Phosphatase-dependent functions. The mechanisms that regulate PTEN protein levels and activities may provide new therapeutic targets for a variety of human tumors.

PTEN has tumor-suppressive effect

In 2018, Chen Guoqiang's group published a research article titled "Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role" in Nature Communications, and found that the nuclear PTEN protein interacts with the mRNA spliceosome. Regulates alternative splicing of mRNA precursors, thereby interfering with the extension and secretion of the Golgi apparatus and exerting its tumor-suppressive effect.

The researchers used protein interaction omics technology to identify 136 proteins that interact with nuclear PTEN. Among them, 38 belong to the constituents of the spliceosome. PTEN tightly binds to spliceosome proteins and regulates spliceosome assembly, and confirmed that PTEN can directly interact with the spliceosome protein U2AF2, affecting its recruitment by the spliceosome.

mRNA splicing is the process of removing introns from precursor mRNAs and splicing exons into mature mRNAs. They are tightly regulated in different tissues and developmental processes, and their disorders are closely related to various diseases. This study found that nuclear PTEN can regulate the alternative splicing of precursor mRNA at an overall level. By analyzing the frequency of these alternative splicing events in tumor samples, their correlation with PTEN, and their relationship with patient survival, it was found that a considerable part of PTEN-regulated alternative splicing events is closely related to the occurrence and development of tumors.

Further research found that alternative splicing of the Golgi-related functional gene GOLGA2 is one of the alternative splicing events regulated by nuclear PTEN. PTEN deletions undergo splicing jumps, resulting in more exon-free variants, which make the Golgi apparatus more stretched and enhance secretory function, which in turn mediates the growth advantage of PTEN-deficient tumors. The researchers used the secretion inhibitors BFA and GCA to selectively kill PTEN-deficient tumor cells. The results revealed a new mechanism by which PTEN protein in the nucleus plays a tumor-suppressive role, and also provided new ideas for targeted therapy of PTEN-deficient tumors.

PTEN's Cancer Promoting Function

However, in the recent issue of the journal Nature Cell Biology, Chen Guoqiang's research group published an article entitled "PTENα and PTENβ promote carcinogenesis through WDR5 and H3K4 trimethylation", reporting that the translational variant PTENα/β of the tumor suppressor protein PTEN has the function of promoting tumors.

New research finds that in addition to encoding the classic PTEN protein, the pten gene can also generate two long-form protein variants, namely, PTENα and PTENβ, by encoding two different atypical translation initiation points, respectively The amino terminus of the protein has an extension of 173 and 146 amino acids.

Through research on liver cancer, it was found that the protein levels of PTEN and PTENα/β in cancer tissues are inconsistent, and there are cases where PTEN decreases but PTENα/β does not change or increases. Through tumor-bearing experiments in nude mice, a completely opposite result was obtained. Unlike the tumor suppressive effect of PTEN protein, PTENα/β can play a tumor-promoting role.

The WDR5 protein recognizes MLL and forms a WRAD core catalytic complex with other proteins (including WDR5, RBBP5, ASH2L, and DYP-30). The complex catalyzes the methylation of histone H3, activates gene transcription and participates in epigenetic regulation. New research finds that PTENα/β can directly interact with WDR5 through the N-terminal extension, maintain the catalytic activity of MLL, promote the methylation of histone H3K4, activate the expression of a series of tumor-promoting genes including NOTCH3, and then play a role in promoting tumor effect.

Unlike classic PTEN proteins, PTENα/β proteins are extremely unstable. Ubiquitin ligase FBXW11 and deubiquitinase USP9X can bind to the N-terminal extension of PTENα/β, specifically regulate the stability of PTENα/β by regulating lysine 235 and 239 ubiquitination and deubiquitination . USP9X can exert a tumor-promoting effect by stabilizing PTENα/β, while FBXW11 can exert a partial tumor-suppressing effect by mediating PTENα/β degradation.

Add This Entry To Your CureZone Favorites!