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• W2000780971 abstract "One of the markers commonly used to identify tumor-suppressor genes is the frequent loss of heterozygosity (LOH) at a particular locus in tumor samples, indicating that at least one of the alleles has been deleted. LOH at chromosome 10q23 has been detected in ∼75% of glioblastomas and in ∼60% of advanced–prostate cancer samples (reviewed in Li et al., 1997Li J Yen C Liaw D Podsypanina K Bose S Wang S Puc J et al.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer.Science. 1997; 275: 1943-1946Crossref PubMed Scopus (4079) Google Scholar; Steck et al., 1997Steck PA Perhouse MA Jasser SA Yung WKA Lin H Ligon AH Lauren AL et al.Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.Nat Genet. 1997; 15: 356-362Crossref PubMed Scopus (2442) Google Scholar), suggesting the presence of a tumor suppressor at this locus. In fact, reintroduction of this region of chromosome 10 into glioblastoma cell lines resulted in a loss of tumorigenicity in nude mice (Pershouse et al., 1993Pershouse MA Stubblefield E Hadi A Killary AM Yung WK Steck PA Analysis of the functional role of chromosome 10 loss in human glioblastomas.Cancer Res. 1993; 53: 5043-5050PubMed Google Scholar; Steck et al., 1995Steck PA Ligon AH Cheong P Yung WK Pershouse MA Two tumor suppressive loci on chromosome 10 involved in human glioblastomas.Genes Chromosom Cancer. 1995; 12: 255-261Crossref PubMed Scopus (89) Google Scholar). Recently, a candidate tumor-suppressor gene, termed “PTEN” (“phosphatase and tensin homologue deleted from chromosome 10”) or “MMAC1” (“mutated in multiple advanced cancers”), has been isolated from chromosome 10q23 (Li et al., 1997Li J Yen C Liaw D Podsypanina K Bose S Wang S Puc J et al.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer.Science. 1997; 275: 1943-1946Crossref PubMed Scopus (4079) Google Scholar; Steck et al., 1997Steck PA Perhouse MA Jasser SA Yung WKA Lin H Ligon AH Lauren AL et al.Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.Nat Genet. 1997; 15: 356-362Crossref PubMed Scopus (2442) Google Scholar). Importantly, in the majority of glioblastoma samples in which only one allele had been deleted, the other allele contained point mutations or small deletions, suggesting that disruption of both alleles is necessary for the formation of glioblastomas. Although the sample sizes used currently are small, LOH and/or point mutations have been found in PTEN in a growing number of tumor samples, including ∼50% of endometrial cancers (Tashiro et al., 1997Tashiro H Blazes MS Wu R Cho KR Bose S Wang SI Li J et al.Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies.Cancer Res. 1997; 57: 3935-3940PubMed Google Scholar), suggesting that disruption of PTEN is necessary for the development of specific forms of cancer. Strong evidence that PTEN is a bona fide tumor suppressor comes from a recent flurry of papers that have identified germ-line mutations of PTEN in three related, inheritable, neoplastic disorders: Cowden disease, Lhermitte-Duclos disease, and Bannayan-Zonana syndrome (Liaw et al., 1997Liaw D Marsh DJ Li J Dahia PLM Wang SI Zheng Z Bose S et al.Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.Nat Genet. 1997; 16: 64-67Crossref PubMed Scopus (1617) Google Scholar; Marsh et al., 1997Marsh DJ Dahia PLM Zheng Z Liaw D Parsons P Gorlin RJ Eng C Germline mutations in PTEN are present in Bannayan-Zonana syndrome.Nat Genet. 1997; 16: 333-334Crossref PubMed Scopus (554) Google Scholar; Nelen et al., 1997Nelen MR van Staveren MCG Peeters EAJ Ben Hassel M Gorlin RJ Hamm H Lindboe CF et al.Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.Hum Mol Genet. 1997; 6: 1383-1387Crossref PubMed Scopus (395) Google Scholar). All these disorders share similar pathological traits, such as the formation of multiple benign tumors (mostly hamartomas) and an increased incidence of malignant cancers (Eng et al., 1994Eng C Murday V Seal S Mohammed S Hodgson SV Chaudray MA Fentiman IS et al.Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy?.J Med Genet. 1994; 31: 458-461Crossref PubMed Scopus (88) Google Scholar). Lhermitte-Duclos disease has additional pathologies, such as mental retardation and macrocephaly, whereas Bannayan-Zonana syndrome also includes lipomatosis and speckled penis and has an earlier onset of the disease (Grolin et al., 1992Grolin RJ Cohen MM Condon LM Burke BA Bannayan-Riley-Ruvalcaba syndrome.Am J Med Genet. 1992; 44: 307-314Crossref PubMed Scopus (219) Google Scholar). The nonneoplastic pathologies seen in Cowden disease, Lhermitte-Duclos disease, and Bannayan-Zonana syndrome also indicate that PTEN functions during normal development. One of the interesting aspects of PTEN is that it shares homology with the family of protein tyrosine phosphatases (PTPs) as well as with the cytoskeletal protein tensin (Li et al., 1997Li J Yen C Liaw D Podsypanina K Bose S Wang S Puc J et al.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer.Science. 1997; 275: 1943-1946Crossref PubMed Scopus (4079) Google Scholar; Steck et al., 1997Steck PA Perhouse MA Jasser SA Yung WKA Lin H Ligon AH Lauren AL et al.Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.Nat Genet. 1997; 15: 356-362Crossref PubMed Scopus (2442) Google Scholar). Biochemical analysis of PTEN has revealed that it is a member of the family of dual-specificity protein phosphatases (DSPs) that dephosphorylate serine, threonine, and tyrosine residues (Myers et al., 1997Myers MP Stolarov JP Eng C Li J Wang SI Wigler MH Parsons R et al.PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.Proc Natl Acad Sci USA. 1997; 94: 9052-9057Crossref PubMed Scopus (710) Google Scholar). Significantly, naturally occurring point mutations isolated from tumor samples, as well as from tissue explants from patients with Bannayan-Zonana syndrome, resulted in pronounced inhibition of phosphatase activity, indicating that this activity is necessary in order for PTEN to function as a tumor suppressor (Myers et al., 1997Myers MP Stolarov JP Eng C Li J Wang SI Wigler MH Parsons R et al.PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.Proc Natl Acad Sci USA. 1997; 94: 9052-9057Crossref PubMed Scopus (710) Google Scholar). The identification of PTEN as the tumor suppressor residing on 10q23 has generated a great deal of interest. PTEN represents a tumor suppressor with a defined enzymatic function, and it represents the first PTP to be implicated as a bona fide tumor suppressor. A large number of protein tyrosine kinases (PTKs) have been implicated as oncogenes, and disruption of the signaling components downstream of PTKs has been associated with the transformed phenotype. Since the initial purification and cloning of the PTP family, PTPs have been implicated in the inhibition of cell growth, and it has become apparent that PTPs that are the natural antagonists of the growth-promoting PTKs have been identified. In fact, treatment of normal rat kidney cells with an inhibitor of cellular PTPs resulted in transformation (Klarlund, 1985Klarlund JK Transformation of cells by an inhibitor of phosphatases acting on phosphotyrosine in proteins.Cell. 1985; 41: 707-717Abstract Full Text PDF PubMed Scopus (258) Google Scholar), demonstrating the importance of this class of enzymes in maintaining control of cell proliferation. In addition to proliferation, PTPs have been implicated in a variety of nonneoplastic diseases, including diabetes (Begum et al., 1991Begum N Sussman KE Draznin B Differential effects of diabetes on adipocyte and liver phosphotyrosine and phosphoserine phosphatase activities.Diabetes. 1991; 40: 1620-1629Crossref PubMed Scopus (45) Google Scholar) and myotubular myopathy (Laporte et al., 1996Laporte J Hu IJ Kretz C Mandel JL Kioschis P Coy JF Klauck SM et al.A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast.Nat Genet. 1996; 13: 175-182Crossref PubMed Scopus (481) Google Scholar), and are essential virulence factors for a number of microbrial pathogens (Andersson et al., 1996Andersson K Carballeira N Magnusson KE Persson C Stendahl O Wolf-Watz H Fallman M YopH of Yersinia pseudotuberculosis interrupts early phosphotyrosine signalling associated with phagocytosis.Mol Microbiol. 1996; 20: 1057-1069Crossref PubMed Scopus (129) Google Scholar). Furthermore, PTPs have been implicated in the regulation of immune-cell function (Neel and Tonks, 1997Neel BG Tonks NK Protein tyrosine phosphatases in signal transduction.Curr Opin Cell Biol. 1997; 9: 193-204Crossref PubMed Scopus (719) Google Scholar). PTEN is a member of the PTP family of enzymes. The entire family is characterized by the presence of a catalytic signature motif, HCXXGXXRS/T. In both the PTPs and the DSPs this motif is located within a conserved secondary structure consisting of seven α-helices and 10 β-sheets (Barford et al., 1995Barford D Jia Z Tonks NK Protein tyrosine phosphatases take off.Nat Struct Biol. 1995; 2: 1043-1053Crossref PubMed Scopus (177) Google Scholar). The diversity of the PTP family arises mostly from the sequences that flank this conserved catalytic core and includes extracellular ligand-binding domains and motifs for protein-protein interaction that specifies subcellular localization or motifs for the regulation of enzymatic activity (Zhang et al., 1995Zhang S-H Eckberg WR Yang Q Samatar AA Tonks NK Biochemical characterization of a human band 4.1–related protein tyrosine phosphatase, PTPH1.J Biol Chem. 1995; 270: 20067-20072Crossref PubMed Scopus (21) Google Scholar). Subcellular targeting also may contribute to substrate specificity, by restricting the potential cellular targets. Conventional wisdom suggests that PTPs are promiscuous, but recent evidence has clearly demonstrated that the PTPs exhibit exceptional substrate specificity in a cellular context (Flint et al., 1997Flint AJ Tiganis T Barford D Tonks NK Development of “substrate-trapping” mutants to identify physiological substrates of protein tyrosine phosphatases.Proc Natl Acad Sci USA. 1997; 94: 1680-1685Crossref PubMed Scopus (657) Google Scholar). The presence of transmembrane receptor–like PTPs (RPTPs) suggests that, as with the regulation of the receptor tyrosine kinases, these RPTPs may be regulated by the binding of ligands. In addition, many of the extracellular domains have homology to cell-adhesion molecules, indicating a role for these PTPs in the regulation of biological responses to the extracellular matrix or to cell-cell contact. It is important to note that PTPs can exert both positive and negative regulatory functions and in some cases have been shown to be positive regulators of cell proliferation. For example, two closely related PTPs, SHP-1 and SHP-2 (src-homology domain 2–containing phosphatase), have opposing effects on cell signaling. SHP-1 acts to control cytokine signaling by down-regulating the Janus family of PTKs, whereas SHP-2 is necessary for the growth factor–dependent activation of Ras (reviewed in Neel and Tonks, 1997Neel BG Tonks NK Protein tyrosine phosphatases in signal transduction.Curr Opin Cell Biol. 1997; 9: 193-204Crossref PubMed Scopus (719) Google Scholar). The PTPs and DSPs appear to utilize the same catalytic mechanism. Dephosphorylation is initiated by the active-site cysteine (located in the signature motif), which functions as a nucleophile to attack the phosphorus atom of the substrate, forming a thiol-phosphate intermediate. Another conserved residue, an aspartic acid located ∼32 residues N-terminal to the catalytic cysteine, promotes the release of the dephosphorylated substrate from the enzyme-substrate complex. The active enzyme is regenerated by a water molecule, which attacks the thiol-phosphate bond, liberating the phosphoryl group from the catalytic cysteine (reviewed in Barford et al., 1995Barford D Jia Z Tonks NK Protein tyrosine phosphatases take off.Nat Struct Biol. 1995; 2: 1043-1053Crossref PubMed Scopus (177) Google Scholar). This reaction can proceed very quickly, with PTP1B undergoing ∼2,000 catalytic cycles/min (Flint et al., 1997Flint AJ Tiganis T Barford D Tonks NK Development of “substrate-trapping” mutants to identify physiological substrates of protein tyrosine phosphatases.Proc Natl Acad Sci USA. 1997; 94: 1680-1685Crossref PubMed Scopus (657) Google Scholar), and the Yersinia PTP (YOP) can undergo an astonishing 90,000 catalytic cycles/min! Determination of the crystal structures of PTPs and DSPs has revealed the structural basis for the differences in amino acid specificity. In the PTPs, this catalytic cysteine residue is located at the base of a deep cleft (Barford et al., 1994aBarford D Flint AJ Tonks NK Crystal structure of human protein tyrosine phosphatase 1B.Science. 1994a; 263: 1397-1404Crossref PubMed Scopus (654) Google Scholar). The depth of this cleft is equivalent to the length of a phosphotyrosine residue. The much shorter phosphoseryl and phosphothreonyl residues are unable to reach the base of the cleft, where the nucleophilic attack by the invariant cysteine occurs, and therefore cannot be dephosphorylated. On the other hand, the catalytic cysteine in the DSPs is in a much shallower cleft that can accommodate all three phosphorylated hydroxyl amino acids (Yuvaniyama et al., 1996Yuvaniyama J Denu JM Dixon JE Saper MA Crystal structure of the dual specificity protein phosphatase VHR.Science. 1996; 272: 1328-1331Crossref PubMed Scopus (295) Google Scholar). PTEN possesses intrinsic phosphatase activity and is a member of the dual-specificity family of PTPs (Myers et al., 1997Myers MP Stolarov JP Eng C Li J Wang SI Wigler MH Parsons R et al.PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.Proc Natl Acad Sci USA. 1997; 94: 9052-9057Crossref PubMed Scopus (710) Google Scholar). PTEN prefers extremely acidic substrates, exhibiting almost 50 times more activity toward polyacidic substrates than toward more traditional substrates (Myers et al., 1997Myers MP Stolarov JP Eng C Li J Wang SI Wigler MH Parsons R et al.PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.Proc Natl Acad Sci USA. 1997; 94: 9052-9057Crossref PubMed Scopus (710) Google Scholar). The extreme selectivity of PTEN toward acidic substrates in vitro suggests that the physiological substrates also will be acidic. It is possible that the acidic character may be manifested by proteins that are phosphorylated on multiple sites. Although it is tempting to propose that the physiological substrates of PTEN will be phosphorylated on tyrosine residues, it is important to realize that PTEN may recognize proteins that are exclusively phosphorylated on serine and threonine residues. In this context, it should be noted that the DSP KAP-1 dephosphorylates cdk2 at Thr160 (Poon and Hunter, 1995Poon R Hunter T Dephosphorylation of Cdk2 Thr160 by the cyclin-dependent kinase-interacting phosphatase KAP, in the absence of cyclin.Science. 1995; 270: 90-93Crossref PubMed Scopus (141) Google Scholar). Although the substrates of PTEN in vivo are likely to be proteinaceous, it has been shown that members of this class of enzymes can dephosphorylate a number of nonproteinaceous phosphoesters (Howell et al., 1996Howell LD Griffiths C Slade LW Potts M Kennelly PJ Specificity of IphP, a cyanobacterial dual-specificity protein phosphatase with MAP kinase phosphatase activity.Biochemistry. 1996; 35: 7566-7572Crossref PubMed Scopus (23) Google Scholar), including the 5′ phosphate from RNA (Takagi et al., 1997Takagi T Moore CR Diehn F Buratowski S An RNA 5′-triphosphatase related to the protein tyrosine phosphatases.Cell. 1997; 89: 867-873Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). However, RNA is unlikely to be a target of PTEN, since the capping of RNA occurs in the nucleus, and immunoflourescence analysis has indicated a largely cytoplasmic localization of PTEN (Li and Sun, 1997Li D-M Sun H TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor β.Cancer Res. 1997; 57: 2124-2129PubMed Google Scholar; M. P. Myers, unpublished data). Nevertheless, one should consider acidic nonproteinaceous substrates, such as phosphoinositides, as potential targets for PTEN. Many naturally occurring point mutations in PTEN have been uncovered from tumor samples, tumor cell lines, and germ-line mutations that result in neoplastic diseases (Li et al., 1997Li J Yen C Liaw D Podsypanina K Bose S Wang S Puc J et al.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer.Science. 1997; 275: 1943-1946Crossref PubMed Scopus (4079) Google Scholar; Liaw et al., 1997Liaw D Marsh DJ Li J Dahia PLM Wang SI Zheng Z Bose S et al.Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.Nat Genet. 1997; 16: 64-67Crossref PubMed Scopus (1617) Google Scholar; Marsh et al., 1997Marsh DJ Dahia PLM Zheng Z Liaw D Parsons P Gorlin RJ Eng C Germline mutations in PTEN are present in Bannayan-Zonana syndrome.Nat Genet. 1997; 16: 333-334Crossref PubMed Scopus (554) Google Scholar; Nelen et al., 1997Nelen MR van Staveren MCG Peeters EAJ Ben Hassel M Gorlin RJ Hamm H Lindboe CF et al.Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.Hum Mol Genet. 1997; 6: 1383-1387Crossref PubMed Scopus (395) Google Scholar; Rhei et al., 1997Rhei E Kang L Bogomolniy F Federici MG Borgen PI Boyd J Mutational analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas.Cancer Res. 1997; 57: 3657-3659PubMed Google Scholar; Steck et al., 1997Steck PA Perhouse MA Jasser SA Yung WKA Lin H Ligon AH Lauren AL et al.Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.Nat Genet. 1997; 15: 356-362Crossref PubMed Scopus (2442) Google Scholar; Tashiro et al., 1997Tashiro H Blazes MS Wu R Cho KR Bose S Wang SI Li J et al.Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies.Cancer Res. 1997; 57: 3935-3940PubMed Google Scholar). A number of these point mutations have already been shown to be detrimental to the enzymatic activity of PTEN (Myers et al., 1997Myers MP Stolarov JP Eng C Li J Wang SI Wigler MH Parsons R et al.PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.Proc Natl Acad Sci USA. 1997; 94: 9052-9057Crossref PubMed Scopus (710) Google Scholar). It is possible, on the basis of the conserved secondary structure and catalytic mechanism of the PTPs, to predict how these point mutations disrupt PTEN activity. Point mutations have been found in three major clusters in PTEN (fig. 1). These clusters are also areas that are highly conserved between PTEN and tensin. One cluster surrounds the catalytic motif. Mutations in this region of PTEN are predicted to disrupt enzymatic activity, either by disrupting the catalytic cysteine directly or by altering the orientation of this cysteine in the catalytic cleft, thereby affecting its ability to attack the phosphorus atom (Barford et al., 1994bBarford D Keller JC Flint AJ Tonks NK Purification and crystallization of the catalytic domain of human protein tyrosine phosphatase 1B expressed in Escherichia coli.J Mol Biol. 1994b; 239: 726-730Crossref PubMed Scopus (45) Google Scholar). The second cluster surrounds the conserved aspartic acid residue required for the release of the substrate from the PTP. The third cluster, near the last conserved structural feature of the PTP fold, an α-helix, also disrupts PTEN activity, which is consistent with the proposed role of these residues in coordinating a water molecule that hydrolyzes the thiol-phosphate bond, activating the enzyme for another round of catalysis (Barford et al., 1995Barford D Jia Z Tonks NK Protein tyrosine phosphatases take off.Nat Struct Biol. 1995; 2: 1043-1053Crossref PubMed Scopus (177) Google Scholar; Myers et al., 1997Myers MP Stolarov JP Eng C Li J Wang SI Wigler MH Parsons R et al.PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.Proc Natl Acad Sci USA. 1997; 94: 9052-9057Crossref PubMed Scopus (710) Google Scholar). In addition, a number of point mutations have been found to be spaced throughout the N-terminus of PTEN and are believed to abolish PTEN enzymatic activity, by disrupting the overall secondary structure rather than by specifically disrupting the domains necessary for catalysis (Myers et al., 1997Myers MP Stolarov JP Eng C Li J Wang SI Wigler MH Parsons R et al.PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.Proc Natl Acad Sci USA. 1997; 94: 9052-9057Crossref PubMed Scopus (710) Google Scholar). In addition, two point mutations were tested that did not result in a loss in PTEN enzymatic activity. However, it has not been determined whether these mutations adversely affect the ability of PTEN to function inside cells, perhaps by altering interactions with important regulatory molecules, by altering the ability of PTEN to recognize its physiological substrates, or by adversely affecting the stability of the protein or the message. It is currently unclear why germ-line mutations in PTEN give rise to at least three related, yet distinctive, disorders. Significantly, samples isolated from a Cowden disease patient indicated that the wild-type allele is present in nonaffected tissue but is lost in tumor samples, indicating that the development of tumors is dependent on the secondary mutation of the inherited wild-type allele (Liaw et al., 1997Liaw D Marsh DJ Li J Dahia PLM Wang SI Zheng Z Bose S et al.Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.Nat Genet. 1997; 16: 64-67Crossref PubMed Scopus (1617) Google Scholar). Although the sample size is small, there does appear to be a correlation between the severity of the disorder and the enzymatic activity of the mutated allele (Myers et al., 1997Myers MP Stolarov JP Eng C Li J Wang SI Wigler MH Parsons R et al.PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.Proc Natl Acad Sci USA. 1997; 94: 9052-9057Crossref PubMed Scopus (710) Google Scholar), suggesting that some of these mutations may result in partial-loss-of-function alleles. Similarly, mutations in the RET protein tyrosine kinase have been shown to give rise to at least four different inheritable disorders (van Heyningen, 1994van Heyningen V One gene—four syndromes.Nature. 1994; 367: 319-320Crossref PubMed Scopus (110) Google Scholar). However, other genetic loci that interact with PTEN also may account for the range of phenotypes. Uncovering these other loci will provide important insights into PTEN function, since they are likely to encode members of the same signaling pathway regulated by PTEN, such as the protein kinase(s) that works in opposition to PTEN. Many lines of evidence support the classification of PTEN as a tumor suppressor, especially the finding that germ-line mutations in PTEN result in neoplastic disorders. In addition, PTEN has been found to be mutated in the majority of glioblastomas and advanced prostate cancers and in roughly one-half of endometrial cancers (Li et al., 1997Li J Yen C Liaw D Podsypanina K Bose S Wang S Puc J et al.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer.Science. 1997; 275: 1943-1946Crossref PubMed Scopus (4079) Google Scholar; Steck et al., 1997Steck PA Perhouse MA Jasser SA Yung WKA Lin H Ligon AH Lauren AL et al.Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.Nat Genet. 1997; 15: 356-362Crossref PubMed Scopus (2442) Google Scholar; Tashiro et al., 1997Tashiro H Blazes MS Wu R Cho KR Bose S Wang SI Li J et al.Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies.Cancer Res. 1997; 57: 3935-3940PubMed Google Scholar). However, disruptions in PTEN occur only rarely in breast cancer and in other gynecological cancers (Tashiro et al., 1997Tashiro H Blazes MS Wu R Cho KR Bose S Wang SI Li J et al.Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies.Cancer Res. 1997; 57: 3935-3940PubMed Google Scholar), suggesting that PTEN plays a significant role in the development of only a subset of cancers. Significantly, polymorphisms in PTEN appear to be rare, and mutations that have been identified in PTEN have only been found in neoplastic disorders, strengthening the link between PTEN and neoplastic diseases (Li et al., 1997Li J Yen C Liaw D Podsypanina K Bose S Wang S Puc J et al.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer.Science. 1997; 275: 1943-1946Crossref PubMed Scopus (4079) Google Scholar; Liaw et al., 1997Liaw D Marsh DJ Li J Dahia PLM Wang SI Zheng Z Bose S et al.Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.Nat Genet. 1997; 16: 64-67Crossref PubMed Scopus (1617) Google Scholar; Marsh et al., 1997Marsh DJ Dahia PLM Zheng Z Liaw D Parsons P Gorlin RJ Eng C Germline mutations in PTEN are present in Bannayan-Zonana syndrome.Nat Genet. 1997; 16: 333-334Crossref PubMed Scopus (554) Google Scholar; Nelen et al., 1997Nelen MR van Staveren MCG Peeters EAJ Ben Hassel M Gorlin RJ Hamm H Lindboe CF et al.Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.Hum Mol Genet. 1997; 6: 1383-1387Crossref PubMed Scopus (395) Google Scholar). Determination of the prevalence of PTEN mutations in different kinds of cancer will be necessary to strengthen the statistical link between disruption of PTEN and the formation of specific tumor types. Analysis of tumor samples has resulted in a number of insights into the potential function of PTEN. Disruption of PTEN appears to occur late during tumorigenesis, indicating that PTEN is probably not the so-called transforming event necessary to initiate malignant cell growth. In the case of glioblastoma, LOH at chromosome 10 usually is associated with an amplification and rearrangement of the epidermal growth factor (EGF) receptor (von Deimling et al., 1992von Deimling A Louis DN von Ammon K Petersen I Hoell T Chung RY Martuza RL et al.Association of epidermal growth factor receptor gene amplification with loss of chromosome 10 in human glioblastoma multiforme.J Neurosurg. 1992; 77: 295-301Crossref PubMed Scopus (194) Google Scholar), suggesting that amplification and activation of the EGF receptor was the transforming event, whereas disruption of PTEN may be required at a later stage of tumor progression, perhaps for regulation of a cell-cycle checkpoint that is several steps downstream of the transforming event. However, given the advanced stages at which LOH at chromosome 10q23 occurs in glioblastomas and in prostate cancer, it seems likely that PTEN may function to modulate other cellular processes, such as angiogenesis, that are best detected in tumorigenicity rather than in transformation assays. The homology between PTEN and the cytoskeletal protein tensin suggests that the targets of PTEN may be cytoskeletal. Indeed, a growing body of evidence indicates an important role for tyrosine phosphorylation in the regulation of cytoskeletal function and the importance of cytoskeletal changes during oncogenesis (Cobb and Parsons, 1993Cobb BS Parsons JT Regulation of the cellular src protein tyrosine kinase: interactions of the carboxyl terminal sequences residing between the kinase domain and tyrosine-527.Oncogene. 1993; 8: 2897-2903PubMed Google Scholar; Chrzanowska-Wodnicka and Burridge, 1994Chrzanowska-Wodnicka M Burridge K Tyrosine phosphorylation is involved in reorganization of the actin cytoskeleton in response to serum or LPA stimulation.J Cell Sci. 1994; 107: 3643-3654PubMed Google Scholar). The reversible nature of protein phosphorylation indicates that PTEN will function as a regulatory molecule that acts in opposition to a kinase. Fundamental insights into the biological function of PTEN will be revealed following the identification of its physiological substrates. The identity of these substrates will not only indicate which cellular signaling pathways are normally regulated by PTEN but also may lead to the identification of the potentially oncogenic kinase(s) that is antagonized by PTEN and eventually may lead to the characterization of the entire signaling pathway. There are precedents to illustrate that PTPs function to attenuate signals that normally promote such fundamental responses as growth and proliferation. By removing phosphate, these PTPs act to maintain the balance between an appropriate cellular response to a stimulus and an aberrant, hyperresponsive state that promotes the disease phenotype. Determination of the mechanism by which the opposing forces of PTEN and its antithetic protein kinase function in regulating cellular signaling will provide insights into the maintenance of normal cell physiology and how this is subverted in cancer." @default.
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• W2000780971 title "PTEN: Sometimes Taking It Off Can Be Better than Putting It On" @default.
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