Phosphorylation of middle T by pp60c-src: A switch for binding of phosphatidylinositol 3-kinase and optimal tumorigenesis

Talmage, David A.; Freund, Robert; Young, A. E.; Dahl, Jean S.; Dawe, Clyde J.; Benjamin, Thomas L.

doi:10.1016/0092-8674(89)90869-6

Cited by 177 publications

(136 citation statements)

References 45 publications

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“…One of the best studied sites is that which mediates interactions with the SH2 domains of the p85 subunit of the PI 3-kinase. This enzyme has been shown to associate with the human PDGF P-receptor via tyrosines 740 and 75 1, which lie in the kinase insert region of this receptor (Fantl et al, 1992;Kashishian et al, 1992); with the murine CSF-1 receptor via tyrosine 721 (Reedijk et al, 1992); with tyrosine 315 of polyoma middle T antigen in the mT/pp60C-S" transforming complex (Talmage et al, 1989); and with several phosphorylated tyrosines on the insulin receptor substrate, IRS-1 Yonezawa et al, 1992). All of these tyrosines lie within the consensus sequence YxxM (where x can be a wide range of possible residues).…”

Section: Sh2 Domain-specific Binding Sitesmentioning

confidence: 99%

New insights into protein‐tyrosine kinase receptor signaling complexes

et al. 1993

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Section: Sh2 Domain-specific Binding Sitesmentioning

confidence: 99%

New insights into protein‐tyrosine kinase receptor signaling complexes

et al. 1993

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“…As a consequence, the kinase activity of pp60 c-src , and probably pp62 c-yes , is stimulated (Bolen et al, 1984;Courtneidge, 1985). The activated kinase then phosphorylates tyrosines in MT itself, and these form binding sites for the SH2 domains of the phosphatidylinositol 3'OH kinase (PI3K) 85 kDa subunit (Courtneidge and Heber, 1987;Kaplan et al, 1987;Talmage et al, 1989;Yoakim et al, 1992), the SH2 domain of PLC-g1 (Su et al, 1995), and the PTB domain of Shc (Blaikie et al, 1997;Campbell et al, 1994;Dilworth et al, 1994). These molecules are in turn phosphorylated on tyrosine residues, which stimulates, either directly or indirectly, PI3K (Gorga et al, 1990;Serunian et al, 1990) and PLC-g1 (Su et al, 1995) enzymatic activity.…”

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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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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“…Oncogenic transformation by polyomavirus has been used as a paradigm for the study of mitogenic signaling in mammalian cells since this protein activates many of the cellular pathways also targeted by tyrosine kinase growth factor receptors. Signaling by middle-T requires interactions with cellular proteins such as the serine/ threonine protein phosphatase 2A (PP2A) (Pallas et al, 1990;Walter et al, 1990), Src family tyrosine kinases (Courtneidge and Smith, 1983 and reviewed in Kiefer et al, 1994), the adaptor protein SHC which binds to phosphotyrosine 250 of middle-T via its phosphotyrosine binding (PTB) domain (Dilworth et al, 1994;Campbell et al, 1994), PI 3-kinase (Whitman et al, 1985;Talmage et al, 1989;Courtneidge et al, 1989) and phospholipase Cg-1 (Su et al, 1995). When associated with middle-T, SHC gets phosphorylated at tyrosine residues.…”

Section: Introductionmentioning

confidence: 99%

Protein kinase B/Akt is activated by polyomavirus middle-T antigen via a phosphatidylinositol 3-kinase-dependent mechanism

Meili¹,

Cron²,

Hemmings³

et al. 1998

Oncogene

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The middle tumor antigen (middle-T) of mouse polyomavirus is responsible for the transforming potential of this virus. Middle-T has been shown to interact with a variety of cellular proteins known to mediate mitogenic signaling, like phosphatase-2A, Src family kinases, phosphatidylinositol 3-kinase (PI 3-kinase), the adapter protein SHC, phospholipase Cg-1 and 14-3-3 family proteins. Association with SHC and PI 3-kinase, respectively, stimulates two independent signaling pathways that are indispensible for viral oncogenicity. SHC activates the Ras/MAPK pathway via Grb2/SOS resulting in changes in early gene expression. The downstream targets of PI 3-kinase are less well studied but seem to impinge on serum response factor (SRF) which is also involved in regulating early gene expression. Recently, the protein kinase B/Akt (PKB/Akt) has been identi®ed as a target of PI 3-kinase in receptor tyrosine kinase signaling. Here we show that PKB/Akt is a target of wild type middle-T, but not of mutants unable to activate PI 3-kinase. These data were con®rmed using inhibitors of PI 3-kinase as well as dominant-negative alleles of the catalytic subunit of this lipid kinase. In addition, mutants of PKB/Akt lacking a pleckstrin homology domain and therefore unable to bind to D3 phospatidylinositides were not activated by middle-T. Taken together these data suggest that middle-T activates PKB/Akt in a PI 3-kinase-dependent manner. Furthermore, direct association with D3 phosphatidylinositides seems to be essential for activation of PKB/ Akt.

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Phosphorylation of middle T by pp60c-src: A switch for binding of phosphatidylinositol 3-kinase and optimal tumorigenesis

Cited by 177 publications

References 45 publications

New insights into protein‐tyrosine kinase receptor signaling complexes

New insights into protein‐tyrosine kinase receptor signaling complexes

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

Protein kinase B/Akt is activated by polyomavirus middle-T antigen via a phosphatidylinositol 3-kinase-dependent mechanism

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