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Review
. 2002 Apr;70(4):829-44.
doi: 10.1086/340026. Epub 2002 Mar 1.

Protean PTEN: form and function

Kristin A Waite  1 , Charis Eng
Affiliations
Review

Protean PTEN: form and function

Kristin A Waite et al. Am J Hum Genet. 2002 Apr.

Abstract

Germline mutations distributed across the PTEN tumor-suppressor gene have been found to result in a wide spectrum of phenotypic features. Originally shown to be a major susceptibility gene for both Cowden syndrome (CS), which is characterized by multiple hamartomas and an increased risk of breast, thyroid, and endometrial cancers, and Bannayan-Riley-Ruvalcaba syndrome, which is characterized by lipomatosis, macrocephaly, and speckled penis, the PTEN hamartoma tumor syndrome spectrum has broadened to include Proteus syndrome and Proteus-like syndromes. Exon 5, which encodes the core motif, is a hotspot for mutations likely due to the biology of the protein. PTEN is a major lipid 3-phosphatase, which signals down the PI3 kinase/AKT pro-apoptotic pathway. Furthermore, PTEN is a protein phosphatase, with the ability to dephosphorylate both serine and threonine residues. The protein-phosphatase activity has also been shown to regulate various cell-survival pathways, such as the mitogen-activated kinase (MAPK) pathway. Although it is well established that PTEN's lipid-phosphatase activity, via the PI3K/AKT pathway, mediates growth suppression, there is accumulating evidence that the protein-phosphatase/MAPK pathway is equally important in the mediation of growth arrest and other crucial cellular functions.

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Figures

Figure 1
Figure 1
Germline PTEN mutations in CS, BRRS, PS, and Proteus-like syndromes
Figure 2
Figure 2
Protein domains of PTEN. The N-terminal phosphatase domain (amino acids 1–185) is shown with the catalytic core. The missense mutations which have been crucial for the elucidation of the cellular role of PTEN are highlighted in orange. Mutations at C124 render a lipid- and protein-phosphatase–inactive protein, whereas mutations at G129 result in a lipid-phosphatase–inactive yet protein-phosphatase–active PTEN. The C-terminal domain (amino acids 186–403) contains the lipid-binding C2 domain (amino acids 186–351); PEST domains (amino acids 350–375 and 379–396), which regulate protein stability; and the PDZ domain, which is important in protein-protein interactions. The CK2 phosphorylation sites (S380, T382, and T383), which are important for stability, are indicated by the blue asterisks (*).
Figure 3
Figure 3
PTEN as a regulator of the PI3K pathway. Ligand binding to membrane receptors results in the activation of PI3K and the subsequent increase in PIP3, which recruits PDK1 to the cellular membrane. PDK1 phosphorylates and activates AKT, which in turn regulates a variety of cellular processes. PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT.
Figure 4
Figure 4
PTEN as a modulator of the MAPK pathway. PTEN can inhibit the activation of MAPK by several mechanisms. By dephosphorylating Shc and/or IRS-1, PTEN prevents the association of these proteins to the Sos:Grb complex, which is required for MAPK activation. Gab interacts with the membrane by binding to PI3P regions via the pleckstrin-homology domain. By decreasing the PI3P levels in the membrane, PTEN inhibits the translocation of Gab to the membrane and its subsequent activation of the MAPK pathways. The entire pathway for MAPK activation and protein-protein interactions has been omitted for clarity.
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References

Electronic-Database Information

    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for Charcot-Marie-Tooth syndrome [MIM 118200], BRRS [MIM 153480], CS [MIM 158350], JPS [MIM 174900], PJS [MIM 175200], PS [MIM 176920], congenital hypomyelinating neuropathy [MIM 605253], and PTEN/MMAC1/TEP1 [MIM 601728])

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