PTEN structural analysis assay in bioinformatics 2.
Phosphatase and Tensin Homolog deleted on chromosome 10(PTEN) has been heavily studied since
1997 as a tumor suppressor gene and which is frequently mutated in many type of cancers including
lung, kidney, breast and uterine cancer(Steck et al., 1997). PTEN is the most frequently mutated
tumour suppressor protein after p53 with up to 30% of somatic PTEN mutation occurring in human
tumors. Haplosufficient PTEN germline mutations cause PTEN hamartoma tumor syndrome(PHTS).
PHTS is an umbrella term that include cowden syndrome, BBRS(Bannayan-RileyRuvalcaba syndrome)
and nonsyndromic ASD(autism spectrum disorder) patients with macrocephaly(Paparo et al., 2013).
PTEN predominantly exist in the cytosol and only a fraction is recruited to the plasma
membrane(Yang et al., 2017). Recruitment of PTEN is dependent on the membrane-binding
regulatory interface and is regulated by phosphorylation of PTEN. The major tumor suppressor role
of PTEN is a lipid phosphatase that antagonize the phosphoinositide 3‑kinase/AKT- mammalian
target of rapamycin (mTOR) pathway and thus regulate a plethora of cellular processes including
survival, proliferation and energy metabolism. Consequently, regulation of PTEN is controlled by
post transcriptional modifications, post translational modifications and protein-protein interactions
which are all altered in cancer(Chen et al., 2018).PI3K is a lipid kinase is involved in phosphorylating
phosphatidylinositol-4,5-bisophphate(PIP2) to phosphatidylinositol (3,4,5)-trisphohsate and is
activated by G protein coupled receptors, receptor tyrosine kinases and RAS activation and growth
factors(Milella et al., 2015). PIP3 bind to downstream protein that have plectsrin homology(PH)
domain such as PKB and Akt. PTEN main tumour suppressor activity is dephorlyateing PIP3 to PIP2.
PTEN can have both phosphate dependent and phosphate independent functions.
Structure of PTEN
Human PTEN is a 403 amino acid protein that has 4 main regions; N-terminal PI(4,5)P2 /phosphatase
domain rich in alpha helices, C2 domain rich in beta pleated sheets, carboxyl terminal tail domain
with several phosphorylation sites(C tail) and PDZ binding domain. PTEN also contain the signature
motif HCxxGxxR which is hallmark of the PTPase superfamily. The N terminal portion, 1-185 amino
acids long of the PTEN is homologues to tensin and auxilin.
PTEN acts on G1 cell cycle progression pathway through negative regulation of the PI3-kinase/akt
or PKB signalling pathway. Broad spectrum of neuropsychiatric phenotypes associated with white
matter disease in PTEN hamartoma tumor syndrome.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043120/