What is PTEN protein？
PTEN is a well-known tumor suppressor protein that protects cells from uncontrolled growth and cancer. PI3- kinase and PTEN are the main positive and negative regulators of PI3- kinase pathway regulating growth, survival and proliferation, respectively. These key signal components are the two most common mutant proteins in human cancer, leading to the unregulated activation of PI3K signal, which provides irrefutable genetic evidence for the central role of this pathway in tumorigenesis. PTEN regulates PI3K signaling by dephosphorylating the lipid signaling intermediate PIP3, but PTEN may have additional phosphatase independent activity and other functions in the nucleus.
Figure 1.Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an antagonist of class I phosphatidylinositol 3–kinase (PI3K) signaling. (Chalhoub N, et al. 2009)
Phosphatidylinositol 3-kinase (PI3K) pathway.
The phosphatidylinositol 3-kinase (PI3K) pathway is evolutionarily conserved from yeast to mammals. In higher eukaryotes, PI3K pathway regulates a variety of cellular processes, including metabolism, survival, proliferation, apoptosis, growth and cell migration. It also participates in specific context-sensitive functions. PI3K is a family of intracellular lipid kinases that can phosphorylate phosphatidylinositol and phosphatidylinositol 3-hydroxyl groups. PI3K was divided into three groups according to its structure and substrate specificity. Class I PI3Ks mainly phosphorylates phosphatidylinositol 4-diphosphate (PIP2) to form lipid second messenger phosphatidylinositol-3-mine 4-phosphatidylinositol (PIP3). IA PI3K is activated by growth factor receptor tyrosine kinase (RTK). IA members are heterodimers of regulatory subunits and p110 catalytic subunits. In mammals, IA PI3K transduces signals from insulin and growth factors to regulate proliferation, survival, growth and glucose homeostasis. II and III PI3K use phosphatidylinositol as substrate to produce PI-3-P. In mammals, the pathway is more complex due to the evolution of multiple family members of some effectors and the diversity of growth factors that transmit signals through PI3K in a context-sensitive manner. In response to extracellular signals, class I PI3K catalytic subunits are recruited to activated membrane receptors through their regulatory subunits. Activated PI3Ks catalyzes PIP2 to form PIP3, while lipid phosphatase PTEN directly antagonizes the activity of PI3Ks by dephosphorylating PIP3 to PIP2 (figure 1), thus playing a central negative regulation role of PI3K. PIP3 transmits activation signals by binding to Pleckstrin homologous (PH) domains of proteins, thus recruiting them to the membrane. Serine-threonine kinase AKT (also known as PKB) is the core and important downstream effector of PIP3. AKT is recruited to the membrane by binding to the PIP3 of its PH domain and is completely activated after threonine 308 and serine 473 are phosphorylated by rapamycin-insensitive mTOR complex, or in some cases may be activated by other kinases.
Figure 2. PI3K signaling pathway. Activated RTKs recruit and activate PI3K, leading to increased PIP3 levels. (Chalhoub N, et al. 2009)
Table 1. Incidence of PTEN and PIK3CA mutations in human cancer (Chalhoub N, et al. 2009)
The relationship between PI3K pathway and cancer in 1980s, when the lipokinase activity of PI3K pathway was related to the src protein of two kinds of oncoprotein sarcoma virus and the middle T protein of polyoma virus, a clear relationship was established between PI3K pathway and cancer. SH2-containing p85 binds to phosphotyrosine on viral oncoprotein, recruiting p110 catalytic subunit into these carcinogenic cell complexes, resulting in the activation of this pathway. Similarly, PI3K is activated by RTK, including several carcinogenic growth factor receptors, such as epidermal growth factor receptor, platelet-derived growth factor receptor and mesenchymal epithelial transfer factor, indicating that this pathway is involved in cancer-related signal transduction. The p110a subtype with component activity was isolated from the oncogenic avian retrovirus ASV16 genome, which provided conclusive evidence for the tumorigenicity of PI3K. Most importantly, somatic mutations in human cancer specifically target p110PTEN and α at very high frequencies, resulting in increased activity of PI3K signaling pathways and providing clear genetic evidence for the core role of PI3K in human cancer (Table 1).
What is the biological composition of PTEN?
PTEN is a cytoplasmic protein recruited to the membrane and plays the role of dephosphorylation of PIP3 on the membrane. PTEN may be directed to the membrane through interaction with many membrane-anchored proteins, including MAGI, PAR-3, MAST, SAST, NHERF and NEP; through their PDZ interaction motifs, and through PIP2 binding. PTEN membrane recruitment may be very short-lived because a few milliseconds are enough to dephosphorylate PIP3 and antagonize the PI3K signal. Based on the use of green fluorescent protein fusion protein, the subcellular localization of PTEN was initially reported as cytoplasm. However, different results from several reports show that PTEN is located between the nucleus and the cytoplasm, or only in one of the two intervals. This difference in localization may be due to different cell types or environments, PTEN mutations that affect localization and technical problems, including the use of epitope tags, overexpressed proteins, or differences in endogenous protein antibodies. There are many clear examples that PTEN can be easily displayed in two compartments.
Figure 3.Regulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) protein stability and localization. (Pandey M, et al. 2016)
From figure 3, we can see that PTEN can be regulated by several mechanisms, including phosphorylation and ubiquitin, which control its stability and activity through its subcellular localization. When PTEN is phosphorylated at the C-terminal, PTEN adopts a closed conformation, which increases its stability but decreases its activity. On the contrary, dephosphorylation of PTEN leads to its recruitment on the membrane, where it may interact with proteins containing PDZ domains through its PDZ interaction motifs. The activity of membrane-related PTEN is high, but its stability is poor. In addition, NEDD4-1-mediated ubiquitin can regulate PTEN reversal. Polyubiquitin PTEN is retained in the cytoplasm and degraded by proteasomes, while the ubiquitin of PTEN seems to regulate the entry of PTEN into the nucleus.
PTEN is a hot star molecule in tumor research. Because it can inhibit the activity of phosphatidylinositol-3-kinase through lipid phosphatase, it has become one of the important tumor suppressor genes. Creative Biomart provides PTEN pathway Proteins, from a variety of sources, grades and formulations to facilitate your efficient and accurate research content in the experiment.