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Biological Description
| Specificity | PTEN Antibody (Rabbit mAb) [E1G6] detects endogenous levels of total PTEN protein. |
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| Background | PTEN, phosphatase and tensin homolog deleted on chromosome ten, also known as MMAC, is a lipid phosphatase built from an N-terminal PTP-type catalytic phosphatase domain, a midsection C2 domain that mediates phospholipid membrane interaction, and a fifty-residue, largely unstructured C-terminal regulatory tail; crystal structure analysis of the core catalytic-C2 region reveals intimate, direct interaction between these two domains, though the flexible C-terminal tail is omitted from this structure due to its unstructured nature in the unphosphorylated state. PTEN's principal substrate is the phosphoinositide PIP3, generated by PI3-kinase activation, and PTEN dephosphorylates this lipid back to PIP2, making PTEN the primary negative regulator opposing PI3K output within the PI3K/Akt signaling axis. PTEN catalytic activity and membrane engagement are directly controlled by a cluster of four phosphorylation sites within the C-terminal tail, Ser380, Thr382, Thr383, and Ser385, catalyzed by the protein kinases casein kinase 2 and/or glycogen synthase kinase 3 beta. Semisynthetic reconstitution of individually defined phospho-forms of PTEN shows that tetra-phosphorylation of this C-terminal cluster drives the tail to fold back and bind directly onto the C2 domain, producing a closed, autoinhibited conformation; this closed state substantially reduces PTEN's affinity for membrane phospholipids and correspondingly reduces its lipid phosphatase activity toward PIP3, while simultaneously increasing PTEN protein stability by diminishing its ubiquitination by the E3 ligase WWP2. Molecular dynamics simulation of this phosphorylated closed state shows that the C-terminal tail's collapse over the C2 domain induces long-range conformational rearrangements that extend to and directly perturb the catalytic active site itself, explaining at a structural level why tail phosphorylation reduces enzymatic output even though the phosphorylated residues lie physically distant from the catalytic pocket. Because Ala substitution at this same Ser380/Thr382/Thr383/Ser385 cluster drives PTEN constitutively to the plasma membrane in cellular assays, this phosphorylation-dependent open-closed conformational switch functions as a defined, reversible mechanism controlling PTEN's subcellular localization and activity independent of any change in PTEN protein level. PTEN is frequently expressed at reduced but still wild-type levels in cancer rather than genetically inactivated, and because this phospho-tail-C2 domain interaction is structurally separable and druggable, small molecules capable of disrupting the closed conformation or inhibiting CK2/GSK3beta represent a defined therapeutic strategy for restoring PTEN lipid phosphatase activity in PIP3/Akt-driven tumors. |
Usage Information
| Application | WB, IP, IHC | Dilution |
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| Reactivity | Human, Mouse, Rat, Monkey, Dog | ||||||||
| Source | Rabbit Monoclonal Antibody | MW | 47 kDa | ||||||
| Storage Buffer | PBS, pH 7.2+50% Glycerol+0.05% BSA+0.01% NaN3 | Storage (from the date of receipt) |
-20°C (avoid freeze-thaw cycles), 2 years | ||||||
References
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