Abstract
PTEN (Phosphatase and Tensin homologue) is a 403aa long dual specificity phosphatase and member of the broad protein tyrosine phosphatase family, which has both lipid and protein phosphatase activity. In this chapter, we will discuss in detail the structure, regulation, and mechanism of action of PTEN and its role in cell signaling. The expression and activity of PTEN protein are dysregulated in most of the human neoplastic processes. The gene that encodes for this protein, PTEN, is located at 10q.23. The expression of PTEN gene is altered in tumorigenesis due to multiple factors that affect the transcription and post-translational modification of the gene. It is one of the most widely studied tumor suppressor genes. The PTEN crystal structure possesses an N-terminal phosphatase domain, which is followed by a tightly associated C terminal C2 domain. Transcriptional, epigenetic, and post-translational factors regulate the expression of PTEN protein. PPARγ (Peroxisome proliferator - activated receptor-γ), EGR-1 (Early Growth response transcription factor -1), p53 and Sprouty homologue 2 (SPRY2) positively regulate transcription of PTEN gene. The 17β - estradiol, NF-ΚB, c-JUN are some of the transcription factors that downregulate PTEN expression. The transcription and translation of PTEN can be affected by the epigenetic processes, including DNA methylation, histone acetylation, miR-21 and miR-494. The post-translational modification involves the phosphorylation at serine and threonine residues and oxidation at cysteine residues to alter the conformation and thus activity of PTEN protein. Certain proteins, including androgen receptors, MAGK-1/2/3 (Membrane-associated guanylate kinase), ROCK/SIP2 (Rho-associated protein kinase), LKB-1 (liver kinase B1), and PICT-1(protein interacting with carboxyl terminus 1), bind to PTEN and regulate its activity (Table 1). PTEN acts mainly by dephosphorylating phosphoinositides, which act as second messengers and hence influence cell signaling pathways involving Akt/PKB and MAPK. PTEN also acts as a phosphatase of proteins, such as focal adhesion kinase, Src homology 2 domain-containing (Shc), ETS-2 protein, and influences integrin signaling, Ras-Raf-MAPK pathway and expression of cyclin D. PTEN possesses a phosphatase-independent activity by which it binds to proteins, such as p53, stabilizing it and augmenting its function. These actions of PTEN regulate critical cellular functions, such as cell survival, division, motility and genomic integrity. Hence, PTEN is vital for normal cellular function, acting as an important tumor suppressor and controlling uncontrolled cell proliferation.