Transformation by the v-fms oncogene product: role of glycosylational processing and cell surface expression.

Nichols, Everett J.; Manger, R; Hakomori, Sen‐itiroh; Herscovics, Annetté; Rohrschneider, Larry R.

doi:10.1128/mcb.5.12.3467

Cited by 64 publications

(39 citation statements)

References 58 publications

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“…Because the di erent receptors were made at a comparable rate (Figure 3) it follows that immature as well as mature mutant receptors were rapidly degraded. In support of this we found that, as expected, the glycosylation inhibitor castanospermine blocked the processing of the normal M-CSF receptor (Nichols et al, 1985), but did not inhibit the degradation of mutant D802V receptors (data not shown). Figure 4a (lanes 1 ± 3) is a pulse-labelling study which demonstrates that most of the normal, immature 130 kD protein labelled in 30 min was converted to the mature form after a 90 min chase period ( Figure 4a, lane 2).…”

Section: Receptor Expressionsupporting

confidence: 84%

“…There is evidence that cell surface expression of vFms is required for ®broblast transformation, possibly because v-Fms needs to activate key substrates at the cell membrane (Nichols et al, 1985;Roussel et al, 1984;Hadwiger et al, 1986). The correlation between lack of cell surface expression of the mutant 802 receptors and their inability to transform ®broblasts is particularly strong (compare Figure 1 and Figure 2b).…”

Section: Cell Speci®c Phenotypementioning

confidence: 96%

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Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation

et al. 1999

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Expression of a receptor for human macrophage-colony stimulating factor (M-CSF or CSF-1), containing a point mutation which changes an aspartate to a valine at position 802 of the activating loop of the kinase domain, potently transforms the haemopoietic cell line FDC-P1 yet prevents Rat-2 ®broblast transformation. In order to understand this apparent paradox, aspartate 802 was changed by cassette mutagenesis to each of the other 19 amino acids. All hydrophobic amino acid substitutions were transforming when tested in FDC-P1 cells yet inactivating when tested in Rat-2 ®broblasts. These same amino acid substitutions also activated receptor degradation, strongly suggesting a causal relationship between receptor degradation and inactivation in ®broblasts. Point mutations or small deletions of Y708 within the kinase insert region of the mutant D802V receptor partly inhibited receptor degradation. The more stable D802V receptor derivatives were able to transform both FDC-P1 cells and Rat-2 ®broblasts, so establishing that the cell speci®c e ect of the c-fmsD802V activating loop mutation is attributable to receptor degradation which accompanies kinase activation and prevents the transformation of Rat-2 but not of FDC-P1 cells.

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Section: Receptor Expressionsupporting

confidence: 84%

Section: Cell Speci®c Phenotypementioning

confidence: 96%

Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation

et al. 1999

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“…Figure 4a depicts anti-phosphotyrosine antibody staining of CSF-1 treated pZen cells showing reactivity with a predominantly membrane protein. The punctate pattern is consistent with association of CSF-1R with coated pits on the cell surface (Manger et al, 1984;Nichols et al, 1985). Figure 4b shows the virtually identical¯uorescent pattern seen with aPY723.…”

Section: Immunocytochemistry and Immunohistochemistrysupporting

confidence: 55%

Recognition of activated CSF-1 receptor in breast carcinomas by a tyrosine 723 phosphospecific antibody

et al. 1997

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“…In this context it was of interest to study the phosphorylation pattern of the fms polypeptides from castanospermine-treated cells. It has been shown previously that the glycoprotein-processing inhibitor caused the synthesis of an immaturely glycosylated fms species, designated gpl25cast-v-fms (3,9). Figure (3) as derived from 32P1-labeled cells.…”

mentioning

confidence: 99%

gp140v-fms molecules expressed at the surface of cells transformed by the McDonough strain of feline sarcoma virus are phosphorylated in tyrosine and serine.

Tamura¹,

Simon²,

Niemann³

et al. 1986

Mol. Cell. Biol.

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Cells transformed by the McDonough strain of feline sarcoma virus express at their surface a v-fms-specific transmembrane glycoprotein designated gpl40v-fns. By labeling with 32p;, gpl40v-fFs was shown to be phosphorylated 30-fold more in serine residues than were the cytosolic v-fms polypeptides gpl8]w-finS and gp120v-f1". By using the phosphotyrosine phosphatase-specffic inhibitor sodium orthovanadate, an additional tyrosine phosphorylation was observed in vivo, again involving predominantly gpl40v-fFs. In vitro studies showed that the v-fms proteins were phosphorylated by protein kinase C in a calcium-and phosphatidylserinedependent manner.The McDonough strain of feline sarcoma virus (SM-FeSV) encodes a gag-fms fusion protein (gpl80(a9-fms) which exhibits the typical features of a transmembrane glycoprotein: it is cotranslationally N-glycosylated and processed by proteolytic cleavage to generate p555a5 and gpl2Ov-fms. gpl20v-fms is specified entirely by the viral oncogene v-fms and remains membrane associated. About 10 to 15% of the molecules are transported to the plasma membrane and concomitantly processed by additional glycosylation of the amino-terminal domain to yield gpl40v-fms (1,8,10,12). It has been reported previously that the extracellular domain of gpl40-fms binds the colony-stimulating factor 1 of macrophages (13). In addition, this domain plays a crucial role in regulating the growth offms-transformed cells (3). Although the cytoplasmic domain of the fms gene product exhibits partial sequence homology with other retroviral transforming proteins that exhibit tyrosine-specific kinase activity (4), tyrosine kinase activity has previously only been demonstrated in vitro (2).Effects of sodium orthovanadate on the biosynthesis and the phosphorylation of v-fms-molecules in vivo. Sodium orthovanadate is a potent inhibitor of phosphotyrosinespecific phosphatases (7,14). To study the effects of vanadate on the biosynthesis and phosphorylation of the v-fmsspecific glycoproteins in vivo, we labeled sister cultures of SM-FeSV-transformed NRK cells (G2-NRK-CJS) with 100 pCi of [3H]leucine per ml (Fig. la), 100 ,uCi of [6-3H]glucosamine per ml (Fig. lb), or 1 mCi Of 32p; per ml ( Fig. lc) in the presence or absence of vanadate and analyzed cleared cellular lysates by immunoprecipitation as described previously (15).Figure la shows that gpl2ov-fms represented the most abundantfms species. About 10% of thefms molecules were present as the mature form gpl4Ov-fms which is associated with the plasma membrane (1, 8). The presence of sodium orthovanadate in the labeling medium (Fig. la, lane 3) did not alter the rate of synthesis or the proportions of the individual fms polypeptides. Metabolic labeling under simi-* Corresponding author. lar conditions with glucosamine indicated that glycosylation and processing of the carbohydrate side chains were also not affected by the presence of the phosphatase inhibitor (Fig. lb). This finding suggests that the intracellular transport is not affected by vanadate.Two surprisi...

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Transformation by the v-fms oncogene product: role of glycosylational processing and cell surface expression.

Abstract: The effect of glycosylational-processing inhibitors on the synthesis, cell surface expression, endocytosis, and

Cited by 64 publications

References 58 publications

Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation

Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation

Recognition of activated CSF-1 receptor in breast carcinomas by a tyrosine 723 phosphospecific antibody

gp140v-fms molecules expressed at the surface of cells transformed by the McDonough strain of feline sarcoma virus are phosphorylated in tyrosine and serine.

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