Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase

Otsu, Masayuki; Hiles, Ian D.; Gout, Ivan; Fry, Michael; Ruiz-Larrea, Fernanda; Panayotou, George; Thompson, Andrew R.; Dhand, Ritu; Hsuan, J. Justin; Totty, Nicholas F.; Smith, Anthony D.; Morgan, Sarah J.; Courtneidge, Sara A.; Parker, Peter J.; Waterfield, Michael D.

doi:10.1016/0092-8674(91)90411-q

Cited by 759 publications

(453 citation statements)

References 92 publications

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“…Induction of p85-associated PI3-K activity in the membrane fraction of T. parva-transformed B cells Class I PI3-K activity can be immunoprecipitated from cell extracts with an antibody directed to its regulatory p85 subunit (Otsu et al, 1991). To address the question as to whether infection leads to modulation of host cell PI3-K activity in the course of Theileria-induced B-cell transformation, we quantified p85-associated PI3-K activity in the membrane fraction of parasitized proliferating B cells and compared it with that observed in drug-cured B lymphocytes (see Experimental procedures).…”

Section: Resultsmentioning

confidence: 99%

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

et al. 2000

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SummaryTheileria is an intracellular parasite that causes lymphoproliferative disorders in cattle, and infection of leucocytes induces a transformed phenotype similar to tumour cells, but the mechanisms by which the parasite induces this phenotype are not understood. Here, we show that infected B lymphocytes display constitutive phosphoinositide 3-kinase (PI3-K) activity, which appears to be necessary for proliferation, but not survival. Importantly, we demonstrate that one mechanism by which PI3-K mediates the proliferation of infected B lymphocytes is through the induction of a granulocyte±monocyte colony-stimulating factor (GM-CSF)-dependent autocrine loop. PI3-K induction of GM-CSF appears to be at the transcriptional level and, consistently, we demonstrate that PI3-K is also involved in the constitutive induction of AP-1 and NF-kB, which characterizes Theileria-infected leucocytes. Taken together, our results highlight a novel strategy exploited by the intracellular parasite Theileria to induce continued proliferation of its host leucocyte.

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Section: Resultsmentioning

confidence: 99%

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

et al. 2000

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“…13, 1993 ificity of P13K for binding sites within certain receptor tyrosine kinases is supported by the derivation of a consensus sequence for sites of interaction with p85a (5) and the demonstration of sequence discrimination by both SH2 domains of p85ot (22,26,38). In addition, the difference in binding specificity between isolated p85 and p85 complexed with p110 has aroused speculation that the p110 subunit of PI3K modulates the binding specificity of the p85 subunit (35). Similarly, alternative expression or assembly of subunits may allow for binding specificity to nonreceptor tyrosine kinases.…”

Section: Discussionmentioning

confidence: 98%

“…It has been suggested that differential expression or assembly of the various P13K subunits may confer binding specificity between receptor tyrosine kinases (22,35). Spec-VOL.…”

Section: Discussionmentioning

confidence: 99%

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The SH3 domain of p56lck is involved in binding to phosphatidylinositol 3'-kinase from T lymphocytes.

Vogel

Fujita

1993

Mol. Cell. Biol.

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Many of the Src-like tyrosine kinases are thought to participate in multiprotein complexes that modulate transmembrane signalling through tyrosine phosphorylation. We have used in vitro binding studies employing bacterially expressed glutathione S-transferase-p561k fusion proteins and cell extracts to map regions on p56kk that are involved in binding to phosphatidylinositol 3'-kinase (P13K). Deletions within the SH3 domain of pS6kk abolished binding of P13K activity from T-cell lysates, whereas deletion of the SH2 domain caused only a slight reduction in the level of P13K activity bound to p56kk sequences. The binding of P13K from T-cell extracts to p56kk was not blocked by antiphosphotyrosine antibodies, but p56-kkbound P13K activity was sensitive to phosphatase treatment. The SH3 domain of p56kk also bound the majority of P13K activity from uninfected chicken embryo fibroblasts. However, a drastically different binding specificity was observed with use of extracts of Rous sarcoma virus v-src-transformed cells, in which the majority of P13K activity bound to the SH2 domain of p56k in a phosphotyrosine-dependent manner. These results suggest that are two modes of PI3K binding to p56kk, and presumably to other Src-like tyrosine kinases. In one mode, PI3K from T cells or uninfected chicken embryo fibroblasts binds predominantly to the SH3 domain of p56kk. In the other mode, involving P13K from Rous sarcoma virus-transformed cells, binding is largely phosphotyrosine dependent and requires the SH2 domain of pS6kk.The Ick gene is a member of the src family of genes, which encode a series of eight closely related protein tyrosine kinases (for a review, see reference 23?. The product of the ick gene is a 56-kDa protein (p561 ) that is expressed predominantly in cells of the lymphoid lineage, primarily T lymphocytes and lymphoid tumor cell lines (28, 30, 37).Expression of p56" has also been observed in human carcinomas of the lung and colon (50).Members of the Src family of tyrosine kinases are characterized by an NH2-terminal unique region followed by three regions that contain different degrees of homology among all members of the family (23, 42). In p561ck, Src homology region 3 (SH3) extends from amino acids 56 to 114. The SH2 domain includes amino acids 115 to 221 and the SH1, or catalytic, domain comprises most of the remainder of the C-terminal half of the protein. Recent evidence indicates that the SH2 region of Src-like kinases functions as a protein association domain that is important in the formation of multienzyme complexes that regulate signal transduction through tyrosine phosphorylation (5, 27).Several proteins have been reported to form complexes with pS6lc in T lymphocytes. The NH2-terminal unique region of p56"kk has been shown to associate with the C-terminal region of two T-cell transmembrane glycoproteins, CD4 and CD8 (3,39,40,45,48). The accessory role of CD4 and CD8 in T-cell signalling has led to the suggestion that p56"'" may participate in antigen-stimulated signal transduction events (18,36)....

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“…A total of 60 sequen~s were extracted from the databank. Seven additional domains (Bovine p85 a andp Nand C.terminal SH2 domains [ 12]; human phosphor yrosine phosphatass (PTP) IC N-and C-termlnal SH2 domains [3]; avian tensln SH2 domain [5]) were obtained from the literature.…”

Section: Introduction Ences May Not Be Made Through Homology Modellinmentioning

confidence: 99%

Conservation analysis and structure prediction of the SH2 family of phosphotyrosine binding domains

1992

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Src homology 2 (SH2) regions arc short (approximately 100 amino acids), non-catalytic domains conserved among a wide variety of proteins involved in cytoplasmic signaling induced by growth factors. It is thought that SHZ domains play an important role in the intracellular response to growth faclor stimulation by binding to phosphotyrosinc containing proteins, In this paper WC apply the techniques of multiple scqucnce alignment, secondary structure prediction and conservation analysis to 67 SH2 domain amino acid sequences. This combined approach predicts seven core secondary structure regions with the pattern /3-a-~-/%&%, identifies those residues most likely to be buried in the hydrophobic core of the native SH2 domain, and highlights patterns of conservation indicative of secondary structural elements. Rcsiducs likely to be involved in phosphotyrosine binding arc shown and orientations of the predicted secondary structures suggested which could enable such residues to cooperate in phosphate hinding. WC propose a consensus pattern that encapsulates the principal conserved features of the SH2 domains. Comparison of the proposed Sli2 domain of ukr to this pattern shows only 12140 matches, suggesting that this domain may not exhibit SH2-like properties.

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Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase

Cited by 759 publications

References 92 publications

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

The SH3 domain of p56lck is involved in binding to phosphatidylinositol 3'-kinase from T lymphocytes.

Conservation analysis and structure prediction of the SH2 family of phosphotyrosine binding domains

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