Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A

Pallas, David C.; Shahrik, Lilian K.; Martin, Bruce L.; Jaspers, Stephen R.; Miller, Thomas B.; Brautigan, David L.; Roberts, Thomas M.

doi:10.1016/0092-8674(90)90726-u

Cited by 573 publications

(450 citation statements)

References 64 publications

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“…This area also binds PP2A (Campbell et al, 1995;Eckhart, 1993, 1995;Pallas et al, 1990;Walter et al, 1990) (see Figure 1). All mutations that disrupt PP2A binding to MT also a ect the MT/src association, indicating that these two interactions are closely related, though it is unclear how or why they are linked.…”

Section: Introductionmentioning

confidence: 97%

“…It is now clear that MT transforms cells by stimulating many of the pathways used by tyrosine kinase associated growth factor receptors (Dilworth, 1995), and so can be used to study receptor signalling. MT binds the regulatory, A, and catalytic, C, subunits of protein phosphatase 2A (PP2A) (Pallas et al, 1990;Walter et al, 1990), and three members of the srcfamily of tyrosine kinases, pp60 c-src (Courtneidge and Smith, 1983), pp62 c-yes (Kornbluth et al, 1987), and pp59 c-fyn (Cheng et al, 1988;Horak et al, 1989;Kypta et al, 1988). As a consequence, the kinase activity of pp60 c-src , and probably pp62 c-yes , is stimulated (Bolen et al, 1984;Courtneidge, 1985).…”

Section: Introductionmentioning

confidence: 99%

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Association between src-kinases and the polyoma virus oncogene middle T-antigen requires PP2A and a specific sequence motif

1999

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Polyoma virus encodes a potent oncogene, the middle Tantigen (MT), that induces cell transformation by copying the actions of tyrosine kinase associated growth factor receptors. A crucial component of MT transformation is its ability to bind and stimulate the activity of src-family kinases. However, the mechanism by which this is achieved remains unclear. Tyrosine phosphorylation of MT by src-kinases then provides binding sites for SH2 and PTB domain containing molecules in a paradigm of receptor action. We present evidence here that the MT/src complex contains equi-molar amounts of PP2A, and that phosphatase activity may be required for the interaction of MT with both PP2A and the srcfamily. PP2A, then, is a necessary component of the MT-src complex. We also show that two motifs in the 185 to 210 region of MT, each consisting of a basic area followed by a serine or threonine, are essential for interaction with src-kinases, but not PP2A. The spacing between the serine or threonine and the basic sequence also appears to be important. Substituting a cysteine residue in place of Thr203 in MT has no a ect on the binding of pp60 c-src , showing that these sites interact with src-kinases by a novel mechanism that does not require phosphorylation.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Association between src-kinases and the polyoma virus oncogene middle T-antigen requires PP2A and a specific sequence motif

1999

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“…To date, three families of genes encoding regulatory B subunits have been cloned. The most prevalent isoform, called PR55, B55, or simply B subunit, is encoded by at least three related genes (Mayer et al, 1991;Pallas et al, 1992). Five genes have been cloned that fall into one closely related gene family of PR61 subunits (also called B56, or B' subunit) (McCright and Virshup, 1995;Tehrani et al, 1996;Zolnierowicz et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastoma-related p107 protein

1999

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The proteins of the retinoblastoma family are potent inhibitors of cell cycle progression. It is well documented that their growth-inhibitory activity can be abolished by phosphorylation on serine and threonine residues by cyclin dependent kinases. In contrast, very little is known about the dephosphorylation of retinoblastoma-family proteins. We report here the isolation, by virtue of its ability to associate with p107, of a novel Protein Phosphatase 2A (PP2A) regulatory subunit, named PR59. PR59 shares sequence homology with a known regulatory subunit of PP2A, PR72, but di ers from PR72 in its expression pattern and its functional properties. We show that PR59 co-immunoprecipitates with the PP2A catalytic subunit, indicating that PR59 is a genuine component of PP2A holo-enzymes. In vivo, PR59 associates speci®cally with p107, but not with pRb. Elevated expression of PR59 results in dephosphorylation of p107, but not of pRb, and inhibits cell proliferation by causing cells to accumulate in G1. These data support a model in which the distinct PP2A regulatory subunits act to target the PP2A catalytic subunit to speci®c substrates and suggest a role for PP2A in regulation of p107.

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“…Although LT and ST share 82 amino acids at their N-terminus, ST has a unique C-terminus that binds and inactivates the protein phosphatase 2A (PP2A) family of serine/threonine phosphatases (Pallas et al 1990;Yang et al 1991). Mutations that render ST unable to inhibit PP2A are greatly reduced in their ability to transform growtharrested rat F111 cells (Mungre et al 1994).…”

Section: Sv40 St Antigen: Perturbing Protein Phosphatase 2amentioning

confidence: 99%

Immortalized cells as experimental models to study cancer

Boehm

Hahn

2004

Cytotechnology

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The development of cancer is a multi-step process in which normal cells sustain a series of genetic alterations that together program the malignant phenotype. Much of our knowledge of cancer biology results from the detailed study of specimens and cell lines derived from patient tumors. While these approaches continue to yield critical information regarding the identity, number, and types of alterations found in human tumors, further progress in understanding the molecular basis of malignant transformation depends upon the generation and use of increasingly sophisticated experimental models of cancer. Over the past several years, the recognition that telomeres and telomerase play essential roles in regulating cell lifespan now permits the development of new models of human cancer. Here we review recent progress in the use of immortalized human cells as a foundation for understanding the molecular basis of cancer.Abbreviations: ALT -alternative lengthening of telomeres; HEK -human embryonic kidney; HMEChuman mammary epithelial cell; HPV -human papillomavirus; hTERT -human telomerase reverse transcriptase; LT -SV40 Large T antigen; PD -population doubling; PP2A -protein phosphatase 2A; RalGEF -Ral guanine nucleotide exchange factor; RAS -activated H-Ras allele; shRNA -short hairpin RNA; ST -SV40 small t antigen; TRF -telomere restriction fragment.

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Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A

Cited by 573 publications

References 64 publications

Association between src-kinases and the polyoma virus oncogene middle T-antigen requires PP2A and a specific sequence motif

Association between src-kinases and the polyoma virus oncogene middle T-antigen requires PP2A and a specific sequence motif

Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastoma-related p107 protein

Immortalized cells as experimental models to study cancer

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