Structural Biochemistry/PTEN

Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene located on chromosome 10 in region 10q23 that is part of the protein tyrosine phosphotase (PTP) gene family. It provides the genetic instructions for producing the tumor suppressor protein of the same name (PTEN) [1] The PTEN protein is involved in the pathway that signals for a cell to stop dividing and triggers apoptosis.[1] It has been found that PTEN is often deleted in multiple types of advanced cancers. Cells without PTEN have higher levels of phosphatidylinositol 3,4,5-trisphosphate and protein kinase B, which is a signal that prevents apoptosis. This signal may also cause the cell cycle to continue.[2] Both of these two actions are characteristic of tumor cells. PTEN also plays a role in preventing cell spreading, thus preventing metastasis, by inhibiting focal adhesion. If the growth cells are unable to attach to something while they growth, they will not be able to survive and continue to spread.


Crystallographic structure of human PTEN. The N-terminal phosphatase domain is colored blue while the C-terminal C2 domain is colored red.[3]

The PTEN protein is made up of 403 amino acids. It contains the HCXXGXXR motif that is characteristic of the active sites of the PTP family. At its 190-amino acid N-terminal, the protein is similar to two other proteins, tensin and auxilin. At the C-terminus, there is a 220-amino acid sequence whose function has not yet been figured out, but it is known that both domains are necessary for proper activity and function of the protein.[3] Recent studies of the C-terminus have scientists believe that the region is necessary for PTEN stability and enzymatic activity.[4] In an experiment, the 50-amino acid tail was deleted and was confirmed to be necessary for stability. However, the activity of the PTEN proteins, with the deleted tail, increased. Phosphorylation sites were found to be located on the tail and the results of the experiment suggest that it is possible that the phosphorylation status of PTEN determines the levels of activity. Using X-ray crystallography, the crystal structure of the PTEN protein has been determined. It has been revealed that in the structure, the phosphatase domain is similar to protein phosphatases but it has an enlarged active site that is also able to interact with a phosphoinositide substrate.[3] This property of the phosphatase domain is the reason that PTEN is able to dephosphorylate lipids which is essential for it to function as a tumor suppressor.[4] PTEN also has a C2 domain that allows the protein to bind to membrane phospholipids and prevent the growth of tumor cells.[3] In virto studies have shown that the C2 domain has an affinity for phospholipid membranes which suggests that the C2 domain may be responsible for positioning the catalytic domain of PTEN to interact with cell membrane.[4]


Since the 1980s, there had been evidence of a tumor suppressor located on chromosome 10.[4] Cytogenetic and molecular analysis showed that in brain, bladder and prostate cancer, partial of all of chromosome 10 had been lost.[4] Then, LOH analysis was used to identify the region 10q23 as the most common region that was lost in prostate cancer. As a ressulf of this finding, many experiments were performed to test the role of chromosome 10 and the region 10q23. The wide-type chromosome was reintroduced into tumor cells and had the effect of reducing the ability of these cells to cause tumors in mice[4]. Then in 1997, Li et al used representational difference analysis (RDA) on breast tumors to generate a probe that would match to chromosome 10q23.[4] Yeast artificial chromosomes that contained the probe were present on the sequence-tagged site were isolated and helped identify deletions in breast xenografts. Then exon-trapping analysis was use to identify two exons that created an open reading frame of 403 amino acids that generated a protein with a region that was homologous in both chicken and cows.[4] Another group was able to identify the same candidate tumor-supporessor gene on 10q23 by performing high-density scans on glioma cells lines. From these scans, it was found that the same deletions occurred across the cells lines and exon trapping was used to identify the exons of the gene.[4] A separate study searching for protein tyrosine phosphatases used PCR to identify this gene. Primers that bind to the phosphatase catalysic domain were used to screen human cDNA libraries and found PTEN. The scientists were able to confirm the role of the gene as a phosphatase.[4] It is recorded that PTEN was officially discovered in 1997[5]


Role in Integrin-Mediated SignalingEdit

Integrins are receptor proteins that are involved in signaling for cell migration and invasion. PTEN shares structure characteristics with tensin, a cytoskeletal protein that is very involved in integrin-signaling complexes. Integrins are involved in tumor growth because malignant tumor cells are invasive and metastatic and carry out this behavior by interacting with the integrin family of cell surface receptors [6] It has been shown that Focal Adhesion Kinase (FAK) co-localizes with integrins at focal adhesions and FAK may play a central role in the signal transduction pathway that integrins trigger.[6] FAK has increased expression in invasive and metastatic tumors and is active when tyrosine phosphorylated upon integrin activation.[6] It has been shown that PTEN interacts to dephosphorylate FAK and thus prevent it from causing integrin-mediated cell spreading, migration, invasion and cytoskeleton organization.[6] PTEN functions to inhibit FAK, and thus prevent the progression of tumor growth and spread.


PTEN may also have a role apoptosis, but the role is not universal in all cell types.[7] Apoptosis is a process where a cell genetically determines whether it goes through cell self-destruction. It is activated by either a presence of a stimulus or by a removal of a stimulus or a suppressing agent[8] It is a normal process that eliminates damaged DNA or unwanted cells. When this process is stopped, it may result in uncontrolled cell growth and tumor formation. In vivo studies has shows that PIP-3 is the main substrate of PTEN. PIP-3 is stimulated by growth factors and if there is accumulation of PIP-3 at the membrane, then it starts to recruit proteins to bind to it.[9] Akt is one of the targets of this recruitment and is a well-known survival factor that is responsible for preventing apoptosis by preventing to release of genes necessary for apoptosis to occur. Therefore, the role of PTEN is to regulate the levels of PIP-3 and keep the level low. In mouse models, it has been observed that loss of PTEN causes PIP-3 and Akt to be hyperactivated which has a dramatic effect on cell survival and proliferation.[9]

DNA Damage RepairEdit

It has been observed that when PTEN was deleted in mouse embryonic firbroblasts, it causes spontaneous DNA double-strand breaks that are unable to be repaired by the cell.[10] PTEN is believed to act on chromatin and regulate Rad51, which is the gene responsible for preventing spontaneous double-strand breaks.[10] Others have argued that regardless of the presences of PTEN, the sensing and repair of DNA double-strand breaks is all the same. However, these experiments used different cell lines, so it is possible that the role of PTEN in controlling DNA double-strand breaks depends on cell line and assays used.[10] More study needs to be done in order to determine the exact role of PTEN. Another possibility of PTEN being involved in DNA damage repair is through the nucleotide excision repair (NER) pathway which is a highly conserved pathway in eukaryotes that is responsible for repairing DNA lesions caused by UV. It has been observed that mice with downregulated PTEN that are exposed to low suberythemal UV radiation are more predisposed to skin tumorigenesis and in humans, PTEN is is downregulated in premalignant and malignant skin lesions.[10] It is believed that PTEN is responsible for promoting XPC transcription in keratinocytes. XPC is a critical protein for the NER pathway and without it, repair of the damaged DNA cannot take place. Another interaction PTEN has been found to be involved in is with Chk1, an important signal transducer in the cell cycle checkpoint pathway that is necessary for the cell cycle to continue after stalled DNA replication.[10] Even thought Chk1 regulates PTEN, PTEN levels can also have an effect on CHk1. Loss of PTEN has been observed to cause impaired Chk1-mediated checkpoint activation. PTEN may also play a cooperative role with another tumor suppressor, p53. PTEN located in the nucleus of the call may interact with p53 to arrest cells upon oxidative damage.[10] PTEN has been found to play a regulating role by controlling the DNA binding activity of p53. Up-regulation of PTEN increases the level of p53 and causes G2/M arrest and apoptosis.[10]

As a Tumor SuppressorEdit

As PTEN mainly functions to inhibit cell growth and signals for apoptosis to occur.[6] It mainly works through dephosphorylation of phospholipids that are signals for cell growth and survival. by inhibiting these phospholipids (such as PIP3), PTEN functions to prevent the cells from any further activity.[6] By keeping PIP-3 levels lows, PTEN is able to regulate the growth and proliferation of cells and prevent them from becoming oncogenic. the structural component of PTEN that is responsible for for its tumor supressive properties is its activity as a lipid phosphatase. In an experiment, the lipid phosphatase activity of PTEN was ablated while the protein phosphatase activity was kept intact. When wild-type PTEN and the mutant PTEN were introduced into a PTEN-null glioblastoma cell line, the cells with wild-type PTEN showed induced growth suppression, while cells with the mutant PTEN did not show such results.[4]


  1. a b "PTEN." Genetics Home Reference. National Institutes of Health, National Library of Medicine, n.d. Web. 11 Nov. 2012. <>
  2. Lodish, Harvey. "Oncogenic Mutations Affecting Cell ProliferationFactor Genes Can Autostimulate Cell Proliferation." National Center for Biotechnology Information. U.S. National Library of Medicine, 18 Dec. -0001. Web. 11 Nov. 2012. <>.
  3. a b c d Lee, Jie-Oh; Yang, Haijuan; Georgescu, Maria-Magdalena; Di Cristofano, Antonio; Maehama, Tomohiko; Shi, Yigong; Dixon, Jack E; Pandolfi, Pier et al. (1999). "Crystal Structure of the PTEN Tumor Suppressor". Cell 99 (3): 323–34. doi:10.1016/S0092-8674(00)81663-3. PMID 10555148. 
  4. a b c d e f g h i j k Simpson, Laura; Parsons, Ramon (2001). "PTEN: Life as a Tumor Suppressor". Experimental Cell Research 264 (1): 29–41. doi:10.1006/excr.2000.5130. PMID 11237521. 
  5. Uzoh, Christopher C.; Perks, Claire M.; Bahl, Amit; Holly, Jeff M.P.; Sugiono, Marto; Persad, Raj A. (2009). "PTEN-mediated pathways and their association with treatment-resistant prostate cancer". BJU International 104 (4): 556–61. doi:10.1111/j.1464-410X.2009.08411.x. PMID 19220271. 
  6. a b c d e f Tamura, M.; Gu, J.; Tran, H.; Yamada, K. M. (1999). "PTEN Gene and Integrin Signaling in Cancer". Journal of the National Cancer Institute 91 (21): 1820–8. doi:10.1093/jnci/91.21.1820. PMID 10547389. 
  7. Dahia, P. (2000). "PTEN, a unique tumor suppressor gene". Endocrine Related Cancer 7 (2): 115–29. doi:10.1677/erc.0.0070115. PMID 10903528. 
  8. Allocati, N.; Di Ilio, C.; De Laurenzi, V. (2012). "P63/p73 in the control of cell cycle and cell death". Experimental Cell Research 318 (11): 1285–90. doi:10.1016/j.yexcr.2012.01.023. PMID 22326462. 
  9. a b Di Cristofano, Antonio; Pandolfi, Pier Paolo (2000). "The Multiple Roles of PTEN in Tumor Suppression". Cell 100 (4): 387–90. doi:10.1016/S0092-8674(00)80674-1. PMID 10693755. 
  10. a b c d e f g Ming, Mei; He, Yu-Ying (2012). "PTEN in DNA damage repair". Cancer Letters 319 (2): 125–129. doi:10.1016/j.canlet.2012.01.003. PMID 22266095.