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mutated in multiple advanced cancers 1; protein tyrosine phosphatase PTEN; phosphatase & tensin homolog deleted on chromosome ten; phosphatase & tensin homolog; phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase & dual-specificity protein phosphatase PTEN (PTEN, MMAC1, TEP1)

Function: - tumor suppressor - acts as a dual-specificity protein phosphatase, dephosphorylating Tyr-, Ser- & Thr-phosphorylated proteins - also acts as a lipid phosphatase, removing phosphate in the D3 position of the inositol ring from a) phosphatidylinositol 3,4,5-trisphosphate b) phosphatidylinositol 3,4-phosphate c) phosphatidylinositol 3-phosphate d) inositol 1,3,4,5-tetrakisphosphate - order of substrate preference in vitro: Ptdins(3,4,5)P3 > Ptdins(3,4)P2 > Ptdins3P > ins(1,3,4,5)P4 - lipid phosphatase activity is critical for its tumor suppressor function - antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides thus modulating cell cycle progression & cell survival - unphosphorylated form cooperates with AIP1 to suppress AKT1 activation - dephosphorylates Tyr-phosphorylated focal adhesion kinase & inhibits: a) cell migration b) integrin-mediated cell spreading c) focal adhesion formation - may be a negative regulator of insulin signaling & glucose metabolism in adipose tissue - phosphorylation results in an inhibited activity towards PIP3 - phosphorylation can both inhibit & promote PDZ-binding - unphosphorylated form interacts with 2nd PDZ domain of AIP1 & with DLG1 & MAST2 in vitro - interacts with MAGI3 - in mouse brain tumor model, PTEN reconstitution a) diminished phosphorylation of protein kinase B/Akt b) induced thrombospondin 1 expression c) suppressed angiogenic activity [3]. phosphatidylinositol 3,4,5-triphosphate +H2O phosphatidylinositol 4,5-bisphosphate + phosphate phosphoprotein + H2O a protein + phosphate protein tyrosine phosphate + H2O protein tyrosine + phosphate Cofactor: Mg+2 Structure: - monomer - the C2 domain binds phospholipid membranes in vitro (Ca+2-independent); Ca+2 binding is important for its tumor suppressor function - contains 1 C2 tensin-type domain - contains 1 phosphatase tensin-type domain Compartment: cytoplasm Expression: - expressed at a relatively high level in all adult tissues, including heart, brain, placenta, lung, liver, muscle, kidney & pancreas - expression induced by p53 [4] - expression is down-regulated by TGF-beta Pathology: - mutations of PTEN are found in a large number of cancers - defects in PTEN are a cause of: a) Cowden disease (Lhermitte-Duclos disease) b) Bannayan-Zonana syndrome c) squamous cell carcinoma of the head & neck d) susceptibility to endometrial cancer e) proteus syndrome f) oligodendroglioma g) VACTERL association with hydrocephalus h) prostate cancer i) macrocephaly/autism syndrome - PTEN is deleted in chromosome 10q23 deletion syndrome Laboratory: - PTEN gene mutation - PTEN mRNA expression in tissue - PTEN protein in cancer

Interactions

molecular events

Related

chromosome 10q23 deletion syndrome MMAC1 or PTEN gene

General

dual specificity phosphatase tyrosine phosphatase, non-receptor type

Properties

SIZE: entity length = 403 aa MW = 47 kD COMPARTMENT: cytoplasm STATE: active state MOTIF: Phosphatase tensin-type {14-185} MOTIF: cysteine residue {C124} C2 tensin-type {190-350} Thr phosphorylation site {T366} Ser phosphorylation site {S370} Ser phosphorylation site {S385} binding site SITE: 401-403 FOR-BINDING-OF: PDZ domain MOTIF: Thr phosphorylation site {T401}

References

  1. Steck PA et al, Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997 Apr;15(4):356-62. PMID: 9090379
  2. Li J et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer Science 275(5308):1943 1997 PMID: 9072974s
  3. Wen S et al. PTEN controls tumor-induced angiogenesis. Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4622-7. PMID: 11274365
  4. Stambolic V et al. Regulation of PTEN transcription by p53. Molecular Cell 8:317-325 2001 PMID: 11545734
  5. Entrez Gene :accession 5728
  6. UniProt :accession P60484
  7. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/PTENID158.html
  8. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=PTEN

Component-of

molecular complex

Databases & Figures

OMIM correlations MORBIDMAP 601728 UniProt P60484 Pfam PF00782 Entrez Gene 5728 Kegg hsa:5728 ENZYME correlations Figures/diagrams/slides/tables related to protein tyrosine phosphatase PTEN