Structural features of the colony-stimulating factor 1 receptor that affect its association with phosphatidylinositol 3-kinase.

Shurtleff, Sheila; Downing, James R.; Rock, Charles O.; Hawkins, S. A. C.; Roussel, Martine F.; Sherr, Charles J.

doi:10.1002/j.1460-2075.1990.tb07417.x

Cited by 143 publications

(104 citation statements)

References 39 publications

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“…However, additional studies performed with mouse NIH3T3 cells provided evidence that the KI domains of both the c-and the vFms tyrosine kinases were dispensable for their mitogenic and transforming activities (Taylor et al, 1989). Along the same lines, Shurtle et al (1990) showed that a deletion of the KI domain from the human c-Fms only reduced its mitogenic potency, again in mouse NIH3T3 cells. On the other hand, van der Geer and Hunter (1993) reported that a single point mutation at position 697 of mouse c-Fms (corresponding the Y696 in v-Fms) abolished the mitogenic signal in Rat2 cells.…”

Section: Discussionmentioning

confidence: 83%

Identification of a second Grb2 binding site in the v-Fms tyrosine kinase

et al. 1997

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Tyrosine autophosphorylation of the v-Fms oncogene product results in the formation of high-a nity binding sites for cellular proteins containing Src homology 2 (SH2) domains. These proteins transduce various mitogenic and morphogenic signals. As reported previously, Y 696 KNI in the kinase insert domain of v-Fms binds to the growth factor receptor bound protein 2 (Grb2), a stimulator of the Ras/Raf1 pathway. Here, we mapped Y 921 TNL within the C-terminal domain of Fms as a novel autophosphorylation site. We demonstrate that this site constitutes a second Grb2 binding site: a recombinant fusion protein (residues 904 ± 944) containing phosphorylated Y921 bound Grb2 from FDCP1Mac11 cell extracts signi®cantly more e ciently than a corresponding protein (residues 617 ± 759) containing Y696. A yeast two-hybrid system which allowed the formation of a functional Fms tyrosine kinase was employed to quantify binding of Grb2. Fms-protein containing either one of the two phosphorylation sites bound Grb2 equally well, binding was increased for proteins carrying both sites. In contrast, the simultaneous substitution of Y696 and Y921 by phenylalanines abolished Grb2 binding. Mouse NIH3T3 cells expressing the Y921F mutant Fms-protein showed a substantially higher content of ®bronectin network than wild-type transformed cells and had largely lost their serum independent growth phenotype.

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Section: Discussionmentioning

confidence: 83%

Identification of a second Grb2 binding site in the v-Fms tyrosine kinase

et al. 1997

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“…Early studies found that a similar DKI mutant expressed in NIH 3T3 fibroblasts showed reduced proliferation. 5,20 However, only in vitro receptor-associated PI3-kinase activity was examined, as neither Grb2 nor Stat1 was known at the time to bind to the CSF-1R and PI3-kinase targets have not been identified. Moreover, it is not clear if the same phenotype would be observed in a physiologically more relevant cell type.…”

Section: Resultsmentioning

confidence: 99%

“…Upon binding, CSF-1 induces CSF-1R tyrosine phosphorylation, leading to the activation of Ras/Erk 4 and Class I A phosphatidylinositol 3-kinase (PI3-kinase) 5 and to the formation of DNA-binding complexes containing signal transducers and activators of transcription (Stat) 1,3,5. 6 The CSF-1R also recruits Src kinases via an autophosphorylation site in the juxtamembrane domain.…”

Section: Introductionmentioning

confidence: 99%

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Lee

States

2006

Cell Death Differ

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Colony-stimulating factor-1 (CSF-1) is essential for macrophage growth, differentiation and survival. Myeloid cells expressing a CSF-1 receptor mutant (DKI) show markedly impaired CSF-1-mediated proliferation and survival, accompanied by absent signal transducers and activators of transcription 3 (Stat3) phosphorylation and reduced PI3-kinase/Akt activity. Restoring phosphatidylinositol 3-kinase (PI3-kinase) but not Stat3 signals reverses the mitogenic defect. CSF-1-induced proliferation and survival are sensitive to glycolytic inhibitors, 2-deoxyglucose and 3-bromopyruvate. Consistent with a critical role for PI3-kinase-regulated glycolysis, DKI cells reconstituted with active PI3-kinase or Akt are hypersensitive to these inhibitors. CSF-1 upregulates hexokinase II (HKII) expression through PI3-kinase, and PI3-kinase transcriptionally activates the HKII promoter. Moreover, HKII overexpression partially restores mitogenicity. In contrast, Bcl-x L expression does not enhance long-term proliferation, although short-term cell death is suppressed in a glycolysis-independent manner. This study identifies robust PI3-kinase activation as essential for optimal CSF-1-mediated mitogenesis in myeloid cells, in part through regulation of HKII and support of glycolysis.

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“…However, this enzyme has been shown to be coimmunoprecipitated with activated PPDGFR (7) CSF-1R (49). Moreover, mutation or loss of autophosphorylation sites located within the respective ki domains of the ,PDGFR (25) and CSF-1R (42,48) has been shown to diminish the ability of these mutant receptors to associate with PI-3 kinase. aPDGFR-associated PI-3 kinase activity was readily detectable and comparable in PDGF-BB-stimulated 32D-aR and aRAki-fms cells (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, a deletion of 58 of 70 residues of the c-fms ki domain was reported not to inhibit its enzymatic or mitogenic activity in response to CSF-1 (45). Moreover, a human CSF-1R Aki mutant was also reported to be partially impaired in its mitogenicity and exhibited a significant although incomplete reduction in its associated PI-3 kinase activity (42). These findings have suggested that specific functions of the ki domains of these structurally similar receptor kinases may differ markedly.…”

mentioning

confidence: 97%

Deletion or substitution within the alpha platelet-derived growth factor receptor kinase insert domain: effects on functional coupling with intracellular signaling pathways.

Heidaran¹,

Pierce²,

Lombardi³

et al. 1991

Mol. Cell. Biol.

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The tyrosine kinase domains of the platelet-derived growth factor (PDGF) and colony-stimulating factor-i (CSF-1)/c-fins receptors are interrupted by kinase inserts (ki) which vary in length and amino acid sequence.To define the role of the ki in the human aPDGF receptor (aPDGFR), we generated deletion mutants, designated aRAki-1 and aRAki-2, which lacked 80 (710 to 789) and 95 (695 to 789) amino acids of the 104-amino-acid ki region, respectively. Their functional characteristics were compared with those of the wild-type aPDGFR following introduction into a naive hematopoietic cell line, 32D. Biochemical responses, including PDGF-stimulated PDGFR tyrosine phosphorylation, phosphatidylinositol (PI) turnover, and receptor-associated PI-3 kinase activity, were differentially impaired by the deletions. Despite a lack of any detectable receptor-associated PI-3 kinase activity, 32D cells expressing oxRAkl-1 showed only partially impaired chemotactic and mitogenic responses and were capable of sustained proliferation in vitro and in vivo under conditions of autocrine stimulation by the c-sis product. 32D transfectants expressing the larger ki deletion (aRAki-2) showed markedly decreased or abolished biochemical and biological responses. However, insertion of the highly unrelated smaller c-fms (685 to 750) ki domain into aRAki-2 restored each of these activities to wild-type aPDGFR levels. Since the CSF-1R does not normally induce PI turnover, the ability of the c-fms ki domain to reconstitute PI turnover in the aRAki-2 transfectant provides evidence that the ki domain of the aPDGFR does not directly couple with this pathway. Taken together, all of these findings imply that their ki domains have evolved to play very similar roles in the known signaling functions of PDGF and CSF-1 receptors.

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Structural features of the colony-stimulating factor 1 receptor that affect its association with phosphatidylinositol 3-kinase.

Cited by 143 publications

References 39 publications

Identification of a second Grb2 binding site in the v-Fms tyrosine kinase

Identification of a second Grb2 binding site in the v-Fms tyrosine kinase

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Deletion or substitution within the alpha platelet-derived growth factor receptor kinase insert domain: effects on functional coupling with intracellular signaling pathways.

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