PTEN Regulation Of PI3K AKN Analysis

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PTEN regulation of PI3K/AKT Pathway
In the first lecture of class we discussed a diagram from Saltiel and Kahn 2001. The diagram presented the phosphoinositide 3-kinase (PI3K) and Serine/Threonine Kinase (AKT)/ Protein Kinase B (PKB) pathway inhibition of the insulin receptor and insulin receptor substrate (IRS) through activation of mammalian target of rapamycin (mTOR) and a recent study reports similar findings (Mathew et al. 2016; Saltiel and Kahn 2001). Activation of PI3K/AKT signaling pathway can be triggered by transmembrane Receptor Tyrosine Kinase (RTK) signaling. When an extracellular growth factor binds to the RTK it dimerizes and triggers autophosphorylation through the homologous interaction of each monomer. The dimerized RTK is
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Lipid phosphatases allow them to localize on the cytosolic side of the plasma membrane (Brito et al., 2015). It is also proposed that PTEN has the ability to stabilize the genome as it is often found to localize inside the nucleus (Brito et al., 2015; Bononi and Pinton 2015). However, more research is required to establish a clear link for this proposition. The PI3K pathway regulates cell proliferation, growth, survival, apoptosis and cell migration (Chalhoub and Baker 2009; Smith et al., 2016). In many human cancers PTEN and PI3K frequently become mutated causing dysregulation of the PI3K pathway that induces cell proliferation while evading apoptosis (Smith et al., 2016). In its traditional role, PTEN regulates phosphatidylinositol 3,4,5-triphosphate (PIP3) by catalyzing the dephosphorylation conversion reaction to phosphatidylinositol 4,5-bisphosphate (PIP2) that results in blocking the downstream effects of the PI3K/AKT/Protein Kinase B (PKB) pathway (Brito et al., 2015; Chen et al., 2016; Saltiel et al., 2001; Smith et al., 2016). Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 and 2 (SHIP1/-2) similarly to PTEN converts PIP3 to PIP2, although it does not known to function as a tumor suppressor it us crucial in insulin signaling (Leslie et al., 2008; Saltiel et al., 2001). Therefore, PI3K activates the AKT/PKB pathway through …show more content…
A study conducted by Smith et al., 2016 examined the structural effects of mutant PTEN on the mechanisms it contributes to disease. Wild type (WT) PTEN was analyzed in silico using Visual Molecular Dynamics (VMD) and used the structure to synthesize mutant PTEN with side-chain modification using a mutator plugin (Smith et al., 2016). The researchers of Smith et al., 2016 generated 13 mutant PTEN protein constructs of each phenotype. The researchers conducted energy minimization for 5 incremental stages to reduce steric interference from torsional strain, which was caused by the mutations (Smith et al., 2016). The energy minimization aided in finding the lowest energy or most stable states of the mutant PTEN constructs that would give the most likely representation of each mutant PTEN phenotype. They used a support vector machine to calculate the mutant PTEN protein change in Gibbs free energy (ΔΔG) change to determine stability (Smith et al., 2016). Smith et al., 2016 also used a technique called Elastic Network Contact Model to examine covalent bond stretching, angle twisting dihedral torsion and any possible non-bonded side-chain interactions. The researchers used the resulting data from these structural analyses experiments to examine the functional relationships of PTEN mutation genotypes compared with the

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