Regulation of c-Fes Tyrosine Kinase and Biological Activities by N-Terminal Coiled-Coil Oligomerization Domains

Cheng, Hui-Teng; Rogers, Jim; Dunham, Nancy A.; Smithgall, Thomas E.

doi:10.1128/mcb.19.12.8335

Cited by 36 publications

(80 citation statements)

References 51 publications

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“…Fes exhibits strong expression in myeloid hematopoietic cells and is activated in response to GM-CSF, IL-6 and other cytokines . Fes expression is su cient to induce di erentiation of K-562 myeloid leukemia cells (Cheng et al, 1999;Yu et al, 1989) and may be required for di erentiation and survival signaling in other myeloid cell lines (Manfredini et al, 1993(Manfredini et al, , 1997. We have observed that Fes strongly induces Stat3 activation following co-expression of the proteins in either 293T cells or using a baculovirus/Sf-9 cell system (Nelson et al, 1998).…”

Section: Stat Activation By Src Kinases In Myeloid Cell Survivalmentioning

confidence: 99%

Control of myeloid differentiation and survival by Stats

et al. 2000

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Hematopoiesis involves a complex array of growth factors that regulate the survival and proliferation of immature progenitors, in¯uence di erentiation commitment, and modulate end-stage cell functions. This minireview is focused on the role of Stat activation in the development of myeloid cells in response to hematopoietic cytokines. Much of the evidence implicating Stats in these cellular processes comes from studies of mutant cytokine receptors selectively uncoupled from Stat activation, dominant-inhibitory Stat mutants, and mice with targeted disruptions of Stat genes. Together these approaches provide strong evidence that Stat activation, particularly of Stat3 and Stat5, plays an important role in myeloid di erentiation and survival. Oncogene (2000) 19, 2612 ± 2618.Keywords: stat; cytokine; di erentiation; survival; tyrosine kinase Mutant cytokine receptors lacking Stat recruitment sites fail to induce di erentiation gp130-based receptor system IL-6 and the related cytokines LIF, CNTF, OSM, IL-11 and CT-1 share structural features and a ect an overlapping set of target cells . The receptors for the IL-6 family of cytokines share a signal transducing subunit known as gp130, which provides a link to multiple signaling pathways via a tyrosine phosphorylation-dependent mechanism. This familiar signaling paradigm, shared by all of the cytokine receptor systems discussed here, is initiated by liganddependent receptor oligomerization, activation of receptor-associated tyrosine kinases, and phosphorylation of speci®c tyrosine residues within the receptor. A subset of these receptor phosphotyrosines recruit cytoplasmic Stats through their SH2 domains. The Stats are then phosphorylated by receptor-associated kinases, inducing dimerization, nuclear translocation, and transcriptional activation at speci®c promoter elements. As described in more detail below, regions of gp130 required for myeloid di erentiation are often required for Stat activation.The cytoplasmic region of gp130 responsible for Stat3 activation is also required for di erentiation signaling in the murine leukemia cell line, M1 . Both IL-6 and LIF induce growth arrest and macrophage di erentiation in this cell line. To avoid the complication of signaling from endogenous gp130, chimeric receptors were constructed in which the cytoplasmic region of gp130 was fused to the extracellular ligand-binding domain of growth hormone. The resulting chimeric receptor generated growth hormone-dependent signals for growth arrest and morphological changes indistinguishable from those of IL-6. Successive C-terminal truncations of the chimeric receptor identi®ed the distal 133 residues of gp130 as critical for the generation of signals for growth arrest, macrophage di erentiation, and Stat3 activation. Phosphorylation of Tyr 126 in this region of gp130 forms a binding site for the Stat3 SH2 domain (Y P XXQ motif) (Stahl et al., 1995). Mutagenesis of this site completely blocked di erentiation signaling and Stat3 activation from the truncated receptor. However, mutagenes...

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Section: Stat Activation By Src Kinases In Myeloid Cell Survivalmentioning

confidence: 99%

Control of myeloid differentiation and survival by Stats

et al. 2000

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“…Considering that exon 7 encodes a portion of p92 c-Fes located between the two coiled-coil domains, that the process of nuclear translocation probably deals with Fes activation and that evidence exists in literature that CC1 and CC2 are invloved in Fes activation (Read et al, 1997;Cheng et al, 1999;Smithgall et al, 1998), we investigated whether the coiled-coil domains of p92 c-Fes have a role in the process of nuclear translocation. The recombinant constructs encoding the aminoterminal domain of c-Fes and its deleted forms are shown in We treated these cells with the differentiation-inducing agents and checked them at confocal microscopy.…”

Section: Subcellular Localization Of P92 C-fes Nh 2 -Terminal Domain mentioning

confidence: 99%

“…The experiment shows that the proteins expressed by a construct missing the CC1 or the CC2 domain are not able to translocate to the nucleus, while the constructs expressing the whole protein or the N-terminal domain are present in the nucleus. coiled-coil domains and that it has been hypothesized that the oligomers are the active form of p92 c-Fes (Read et al, 1997;Smithgall et al, 1998;Cheng et al, 1999), we investigated whether oligomerization is a cytoplasmic or a nuclear event and whether it is required for translocation. To do so, we treated HL60-FLAG-FES cells with the crosslinking agent BS3 and we checked the formation of oligomers in cytoplasmic and nuclear extracts.…”

Section: Subcellular Localization Of P92 C-fes Oligomersmentioning

confidence: 99%

“…The latter are particularly interesting because they do not express endogenous Fes but ectopic expression of this gene has been shown to potentiate myeloid differentiation (Yu et al, 1989). Recent studies suggest that the active form of Fes is oligomeric and that its unique N-terminal region containing the two coiled-coil domains is required for the oligomerization to occur (Read et al, 1997;Cheng et al, 1999). Moreover, it has been shown that p92 c-Fes is able to autophosphorylate in trans and that the major site of autophosphorylation maps at Tyr 713 (Hjermstad et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

“…p92 c-Fes is a protein, 822 amino acids in length and it is composed by three main regions: a unique aminoterminal region containing two coiled-coil domains (CC1, CC2) responsible for the formation of homo-and eterooligomers (Read et al, 1997;Cheng et al, 1999), a central SH2 domain able to recognize and bind specific phosphoproteins (Songyang et al, 1994), a carboxy terminal region bearing an ATP binding site, the kinase domain, able to recognize a specific phosphorylation consensus sequence (Pinna and Ruzzene, 1996) and two sites for tyrosine phosphorylation (Hjermstad et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Requirement of the coiled-coil domains of p92c-Fes for nuclear localization in myeloid cells upon induction of differentiation

et al. 2003

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The nonreceptor tyrosine kinase Fes is implicated in myeloid cells differentiation. It has been observed that its localization can be cytoplasmic, perinuclear, or nuclear. To further characterize this point, we studied Fes subcellular localization in myeloid cell lines (HL60 and K562) and in COS1 cells. Fes was observed in both the nucleus and the cytoplasm of HL60, K562 cells overexpressing Fes and only in the cytoplasm of COS1 cells, suggesting that nuclear localization is cell context dependent. Moreover, in myeloid cells, the treatment with differentiation-inducing agents such as retinoic acid, phorbol esters and vitamin D, is followed by an increase of the oligomeric form of Fes in the nucleus. In fact, oligomerization seems to be necessary for translocation to occur, since Fes mutants missing the coiled-coil domains are not able to form oligomers and fail to localize in the nucleus. The active form of Fes is tyrosine phosphorylated; however, phosphorylation is not required for Fes to localize in the nucleus, since tyrosine kinase inhibitors do not block the translocation process.

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Fes

Smithgall

2002

Wiley Encyclopedia of Molecular Medicine

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Regulation of c-Fes Tyrosine Kinase and Biological Activities by N-Terminal Coiled-Coil Oligomerization Domains

Cited by 36 publications

References 51 publications

Control of myeloid differentiation and survival by Stats

Control of myeloid differentiation and survival by Stats

Requirement of the coiled-coil domains of p92c-Fes for nuclear localization in myeloid cells upon induction of differentiation

Fes

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