Multifunctional Tumor Suppressor PTEN Multifunctional Tumor Suppressor

PTEN crystal structure contains a phosphatase and C2 domain Figure 1. Structure of PTEN. (A) Domain structure of PTEN. (B) The crystal structure of PTEN, with the phosphatase domain (PD; residues 14–185) in pink and the C2 domain (residues 186–351) in cyan. The tartrate molecule bound in the phosphatase active site is shown as van der Waals spheres. The loop missing from the crystal structure between P281 and K313 is shown as a dotted line. (C) Coarse-grained (CG) representation of PTEN. The bound tartrate has been replaced with a CG representation of PI(3,4,5)P3, with the PI(3,4,5)P3 molecule positioned as described in the main text. PTEN Crystal Structure http://www.sciencedirect.com/science/article/pii/S0006349512050801 Missense- residue is where it is: WT vs. Mutant (find it in Cowden’s syndrome) most prevalent one Lumb, C. N., & Sansom, M. S. (2013). Defining the Membrane-Associated State of the PTEN Tumor Suppressor Protein. Biophysical Journal, 104(3), 613-621.

PTEN binds PIP3, a phospholipid substrate = Lumb, C. N., & Sansom, M. S. (2013). Defining the Membrane-Associated State of the PTEN Tumor Suppressor Protein. Biophysical Journal, 104(3), 613-621.

PTEN opposes PI3 Kinase to keep PIP3 levels low PTEN and phosphorylated Akt levels were inversely correlated in the large majority of examined samples, suggesting that PTEN regulates phosphatidylinositol 3,4,5-triphosphates and may play a role in apoptosis.  The studies suggested that the PTEN tumor suppressor modulates G1 cell cycle progression through negatively regulating the PI3K (see 171834)/Akt (164730) signaling pathway, and that 1 critical target of this signaling process is the cyclin-dependent kinase inhibitor p27(KIP1) (600778). J. Clin Oncol. July 15, 2004 vol. 22 no. 14 2954-2963. DOI: 10.1200/JCO.2004.02.141

PTEN regulates the AKT pathway which has multiple biological roles Backman, S., Stambolic, V., & Mak, T. (2002). PTEN function in mammalian cell size regulation. Current opinion in neurobiology, 12(5), 516.

Mice PTEN null ES cells grow excessively with disorganized patterning Embryonic lethal Cristofano, A. D., Pesce, B., Cordon-Cardo, C., & Pandolfi, P. P. (1998). Pten is essential for embryonic development and tumour suppression. Nature genetics, 19(4), 348-355.

Cancers with PTEN mutations occur in a dosage dependent manner Cristofano, A. D., Pesce, B., Cordon-Cardo, C., & Pandolfi, P. P. (1998). Pten is essential for embryonic development and tumour suppression. Nature genetics, 19(4), 348-355. http://www.nature.com/ng/journal/v42/n5/images_article/ng.556-F3.jpg

PTEN is one of the most frequently mutated genes in human cancers Eng, C. (2003). PTEN: one gene, many syndromes. Human mutation, 22(3), 183-198.

Cowden Syndrome : hamartomas, benign tumors due to germline mutations often in PTEN phosphatase catalytic site http://www.hinsdale86.org/staff/kgabric/Disease10/Cowden%20Syndrome/Index1.htm Loss-of-function phosphatase and tensin homologue (PTEN) mutations predispose not only to Cowden syndrome (CS), but also to a group of seemingly clinically disparate disorders that, with CS, are collectively referred to as the PTEN hamartoma tumour syndromes (PHTS). About two-thirds of PTEN mutations in CS are found in exons 5, 7,and 8, with 40% in exon 5, although this exon represents only 20% of the coding sequence. This region encodes the crucial phosphatase core motif. Missense mutations within the phosphatase core motif and missense or nonsense mutations 5' of it seem to be associated with the involvement of five or more organs, suggesting a correlation between mutations in this region of PTEN and disease severity65. Germline PTEN loss LOH Phosphatase domain Insulin in context of growth http://www.hinsdale86.org/staff/kgabric/Disease10/Cowden%20Syndrome/Index1.htm

Cowden Syndrome patients display an increased predisposition for cancer More common in females or males?