Tumorigenesis is the result of abnormal activation of growth programs in the cells. Most oncogene and tumor suppressor gene products are components of signal transduction pathways that control cell cycle entry or exit, promote differentiation, sense DNA damage and initiate repair mechanisms, or regulate cell death programs. PTEN has recently been identified as one of the most frequently mutated tumor suppressors in human cancer that functions primarily as a cytoplasmic phosphatase to regulate crucial signal transduction pathways involving growth, adhesion, migration, invasion and apoptosis (Ref.1). It has been demonstrated to be involved in the regulation of a variety of phenotypes whereas its major function of tumour suppression is achieved by the downregulation of the oncogenic Akt/PKB (Protein Kinase-B) pathway (Ref.2 and 3).
PTEN functions both as a dual specificity protein phosphatase and an inositol phospholipid phosphatase. Although it can dephosphorylate protein substrates such as FAK (Focal Adhesion Kinase) and the adapter protein SHC, PTEN predominant enzymatic activity appears to be the dephosphorylation of phosphoinositides: PI(3,4,5)P3 (Phosphatidylinositol 3,4,5-trisphosphate) and PI(3,4)P2 (Phosphatidylinositol 3,4-bisphosphate) at the D3 positions into PI(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) and PI(4)P (Phosphatidyl Inositol Phosphate) respectively, thus antagonizing the PI3K (Phosphatidylinositiol–3 Kinase) activation (Ref.4 and 5). Loss of PTEN function, either in murine ES (Embryonic Stem) cells or in human cancer cell lines, results in accumulation of PI(3,4,5)P3 and PI(3,4)P2 and the subsequent activation of its downstream effectors, such as PDK-1
(Phosphoinositide-Dependent Kiinase-1), Akt, Btk family tyrosine kinases, PKC (Protein Kinase-C), and GEFs (Guanine Nucleotide Exchange Factors) for the Rho family of small GTPases (Guanosine Triphosphatases): Rac1 and CDC42
The PI3K-->Akt pathway is a well-known oncogenic signaling pathway activated in response to various Growth Factors
and ECM (Extracellular Matrix) proteins. Extracellular interactions trigger signaling from Integrins and Growth Factor Receptors and PI3K is activated. On the other hand, accumulation of PI(4,5)P2 by PTEN leads to the activation of the molecular messengers: IP3 (Inositol Triphosphate) and DAG (Diacylglycerol). Recent evidence places the mTOR (Mammalian Target of Rapamycin) kinase downstream of the PI3K-->Akt signaling pathway, which is upregulated in multiple cancers because of loss of the PTEN. PTEN acts as an antagonist of cell survival by downregulating the Akt pathway through dephosphorylation and thus, inhibition of PI(3,4,5)P3. Maintenance of the PTEN tumor suppressor protein is required to modulate Akt activity and to concomitantly control the transcriptional activity of the anti-apoptotic transcription factor NF-KappaB (Nuclear Factor-KappaB) (Ref.6, and 7).
PTEN suppresses migration of a variety of cell types, including primary human fibroblasts and tumor cells primarily due to its ability to dephosphorylate proteins rather than lipids. The regulation of cell migration and adhesion can be divided into two components: (1) a directionally persistent migratory component promoted by the FAK-->Pxn (Paxillin)-->p130CAS signaling pathway, which involves enhanced orientation of the actin cytoskeleton, increased focal contacts and directional migration; and (2) a random-motility component promoted by association of SHC with GRB2 (Growth Factor Receptor-bound Protein-2) and subsequent activation of the Ras-->Raf-->MEK1/2-->ERK1/2 pathway, which involves a modest increase in F-Actin
levels, random orientation of the actin cytoskeleton and more random cell movement (Ref.8).It therefore emerges that the loss of PTEN activity may confer increased survival ability, proliferative potential, and invasive capacity on cells, and thereby may promote progression towards a more malignant phenotype (Ref.9 and 10).
PTEN expression and function is regulated through the action of various proteins.It enhances p53 transactivation, a relationship that requires the interaction between PTEN and p53 and is PTEN Phosphatase independent. Specifically, PTEN may protect p53 from MDM2-mediated degradation, whereas p53 can enhance the transcription of PTEN. PTEN acts to protect p53 from MDM2-mediated degradation by the Proteasome (Ref.11 and 12). PTEN activity is also enhanced by the membrane-associated guanylate kinase family proteins with multiple PDZ domains: MAGI2
(Membrane Associated Guanylate Kinase, WW and PDZ Domain Containing-2) and MAGI3 (Membrane Associated Guanylate Kinase, WW and PDZ Domain Containing-3). PTEN binds to the PDZ domains MAGI2
and MAGI3 through an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2. Thus, Both MAGI2
and MAGI3 enhance the ability of PTEN to suppress activation FAK, SHC and Akt, thus downregulating cell growth, survival and migration (Ref 13 and 14).
The PTEN tumour suppressor is among the most commonly inactivated or mutated genes in human cancer. Mutations in the gene are frequent in glioblastomas, endometrial carcinoma, melanomas, and prostate cancer. Furthermore, three dominant inherited disorders: Cowden disease, Lhermitte-Duclos disease and Bannayan-Zonana syndrome, are linked to germ line mutations in PTEN (Ref.4). Elucidation of the PTEN pathway stands as a potentially important advance in molecular oncology and the tumor status of PTEN seems to be of utmost importance in determining and monitoring treatment of an array of malignancies when the PTEN pathway has to be targeted for therapeutic intervention using new and/or existing pharmacological agents (Ref.15).