Granulocyte macrophage-colony stimulating factor stimulates both association and activation of phosphoinositide 3OH-kinase and src-related tyrosine kinase(s) in human myeloid derived cells.

Corey, Seth J.; Eguinoa, Alicia; Puyana-Theall, K.; Bolen, Joseph B.; Cantley, Lewis C.; Mollinedo, Faustino; Jackson, Trevor; Hawkins, Phillip T.; Stephens, Len R.

doi:10.1002/j.1460-2075.1993.tb05929.x

Cited by 193 publications

(137 citation statements)

References 67 publications

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“…6). However, GM-CSF is also known to stimulate PI3-K (Corey et al, 1993;Sato et al, 1993). Therefore, it is also possible that some of the constitutive AP-1 and NF-kB activity that typifies Theileriatransformed leucocytes results from the GM-CSF autocrine loop, as both factors can be induced by GM-CSF (Adunyah et al, 1991;Zhang et al, 1998).…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…As a member of the Src family of PTK, Lyn has been found to co-precipitate with p85 in B cell receptor and cytokine-stimulated cells (Corey et al, 1993;Gold et al, 1992;Yamanshi et al, 1992). GST constructs of Lyn have been found to associate with and activate PI 3-kinase ( Pleiman et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Yeast two-hybrid in vivo association of the Src kinase Lyn with the proto-oncogene product Cbl but not with the p85 subunit of PI 3-kinase

Dombrosky-Ferlan

Corey

1997

Oncogene

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Ligand binding of multi-chain antigen receptors and hematopoietin/cytokine receptors results in rapid activation of protein tyrosine kinase (PTK)-dependent signalling molecules such as phosphatidylinositol 3-kinase (PI 3-kinase). Co-precipitation studies have shown that Srcrelated PTK, such as Lyn, associates with the p85 regulatory subunit of PI 3-kinase via SH2 and SH3 domain binding with their cognate ligands. More recent studies have shown that the proto-oncogene product Cbl co-precipitates with p85 following engagement of cytokine and antigen receptors. As opposed to in vitro co-precipitation studies, the yeast two-hybrid screen reveals in vivo protein ± protein interactions. Using the yeast two-hybrid screen, we demonstrate an in vivo association of Lyn's SH3 and SH2 domains with the proline-rich domain of Cbl. Lyn's SH3 and SH2 domains do not interact with p85 in the yeast two-hybrid screen, as would be predicted from glutathione-S-transferase (GST) fusion protein pull-down or co-immunoprecipitation studies from whole cell lysates. However, the SH3 domain of p85 interacts with the proline-rich domain of Cbl. When yeast were transformed with catalytic Lyn, an interaction between p85's SH2 domain and Cbl occurred. From the data, we propose the following three step process of PI 3-kinase activation: (1) complexes of Lyn ± Cbl and Cbl ± p85 exist without ligand stimulation, (2) upon ligand binding, Lyn becomes active and phosphorylates Cbl, and (3) Cbl's tyrosine phosphorylated residue serves as a docking site for the SH2 domains of p85 ± thereby stabilizing the complex and activating PI 3-kinase. The yeast two-hybrid system can be used to dissect the precise mechanisms of in vivo protein ± protein interactions, including those between phosphotyrosine and SH2-containing proteins.

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“…The IL-3/IL-5 and GM-CSF cytokines induce a rapid activation of the lipid kinase phosphatidylinositol-3 kinase (PI3K) (Sato et al, 1993Co er et al, 1998a,b;Corey et al, 1993;Gold et al, 1994;al Shami et al, 1997). Interestingly, the same region of the b c chain that is responsible for the activation of the Ras pathway seems to be involved in signaling via the PI3K pathway (Sato et al, 1993).…”

Section: Pi3k-pkb/akt Pathwaymentioning

confidence: 99%

“…The p80 adaptor protein acts as a sca old that interacts with the b c chain and the p85 subunit of PI3 kinase in IL-3 stimulated cells (Rao and Mufson, 1995;Jucker and Feldman, 1995). This sca old complex also contains members of the Src-kinase family, Yes and Lyn (Corey et al, 1993;Jucker and Feldman, 1995;Torigoe et al, 1992). Downstream proteins recruited by the PI3 kinase pathways upon IL-3 stimulation include the PKB/ AKT protein.…”

Section: Pi3k-pkb/akt Pathwaymentioning

confidence: 99%

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

et al. 2000

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Hematopoiesis is the cumulative result of intricately regulated signal transduction cascades that are mediated by cytokines and their cognate receptors. Proper culmination of these diverse signaling pathways forms the basis for an orderly generation of di erent cell types and aberrations in these pathways is an underlying cause for diseases such as cancer. Over the past several years, downstream events initiated upon cytokine/ growth factor stimulation have been a major focus of biomedical research. As a result, several key concepts have emerged allowing a better understanding of the complex signaling processes. A group of novel transcription factors, termed signal transducers and activators of transcription (STATs) appear to orchestrate the downstream events propagated by cytokine/growth factor interactions with their cognate receptors. Until recently, the JAK proteins were considered to be the tyrosine kinases, which dictated the levels of phosphorylation and activation of STAT proteins, forming the basis of the JAK-STAT model. However, over the past few years, increasing evidence has accumulated which indicates that at least some of the STAT protein activation may be mediated by members of the Src gene family following cytokine/growth factor stimulation. Studies have demonstrated that the Src-family of tyrosine kinases can phosphorylate and activate certain STAT proteins, in lieu of JAK kinases. In such a scenario, JAK kinases may be more crucial to phosphorylation of the cytokine/growth factor receptors and in the process create docking sites on the receptors for binding of SH2-containing proteins such as STATs, Src-kinases and other signaling intermediates. Tyrosine phosphorylation and activation of STAT proteins can be achieved either by JAKs or Src-kinases depending on the nature of STAT that is being activated. This forms the basis for the JAK-Src-STAT model proposed in this review. The concerted action of JAK kinases, members of the Src-kinase family and STAT proteins, leads to cell proliferation and cell survival, the end-point of the cytokine/growth factor stimulus.

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Granulocyte macrophage-colony stimulating factor stimulates both association and activation of phosphoinositide 3OH-kinase and src-related tyrosine kinase(s) in human myeloid derived cells.

Cited by 193 publications

References 67 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

Yeast two-hybrid in vivo association of the Src kinase Lyn with the proto-oncogene product Cbl but not with the p85 subunit of PI 3-kinase

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

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