A point mutation in the extracellular domain of the human CSF-1 receptor (c-fms proto-oncogene product) activates its transforming potential

Roussel, Martine F.; Downing, James R.; Rettenmier, Carl W.; Sherr, Charles J.

doi:10.1016/0092-8674(88)90243-7

Cited by 240 publications

(161 citation statements)

References 31 publications

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“…Activation by a point mutation in the extracellular domain was also reported in the fms and trk receptor tyrosine kinases (3,17,27). Substitution of serine for leucine at codon 301 was detected in the fms gene, resulting in activation of its transforming potential.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Activation of the ret Proto-oncogene by Multiple Endocrine Neoplasia 2A Mutations

Asai

Iwashita

Matsuyama

et al. 1995

Molecular and Cellular Biology

333

224

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The c-ret proto-oncogene encodes a transmembrane tyrosine kinase that contains a cadherin-like structure in the extracellular domain (9,10,19,22,23). Its expression was detected at high levels in the peripheral nervous systems such as the enteric and autonomic nervous systems as well as in the excretory system during embryogenesis (1a, 15, 25). In addition, it is expressed preferentially in human tumors such as neuroblastoma, pheochromocytoma, and thyroid medullary carcinoma (8,18,24). Since the peripheral nervous systems and tumors mentioned above derive from neural crest cells, the physiological function of the c-ret proto-oncogene appears related to their normal growth and differentiation.Recent studies revealed that germ line mutations in the c-ret proto-oncogene are associated with the development of four different neural crest disorders (neurocristopathies): multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma, and Hirschsprung's disease (2,4,5,7,13,16). MEN 2A and MEN 2B are autosomal dominant cancer syndromes characterized by the development of medullary thyroid carcinoma and pheochromocytoma. MEN 2B is distinguished from MEN 2A by a more complex phenotype including mucosal neuroma, hyperganglionosis of the gastrointestinal tract, and marfanoid habitus. MEN 2A and familial medullary thyroid carcinoma mutations always involve cysteine residues present in the extracellular domain of the c-ret proto-oncogene (4, 12, 13). These cysteine residues are conserved in both human and mouse c-ret proto-oncogenes, suggesting that they are important for normal conformation of the c-Ret protein (9,22,23). On the other hand, a single point mutation in exon 16 of the tyrosine kinase domain has been found in 95% of patients with MEN 2B (6). This difference of the mutation sites may account for different phenotypes of MEN 2A and MEN 2B. Alternatively, it is possible that the diverse phenotypes observed in MEN 2A and MEN 2B are due to mutations in other modifier genes.Hirschsprung's disease is a developmental disorder of the enteric nervous system, inherited in an autosomal dominant manner with incomplete penetrance and variant expressivity. Several mutations have been found in different domains of the c-ret proto-oncogene, including the extracellular and tyrosine kinase domains (5, 16). Since mice homozygous for c-ret disruption showed phenotypes similar to Hirschsprung's disease (20), it is likely that the abnormalities observed in Hirschsprung's disease are caused by inactivation of the c-Ret function. On the other hand, MEN 2A and MEN 2B mutations might represent gain-of-function mutations.To elucidate the mechanism of development of MEN 2A syndrome, we introduced MEN 2A mutations in the extracellular domain of the c-ret proto-oncogene and analyzed their functions. Biochemical analysis of the Ret protein with MEN 2A mutations indicated that it is activated by ligand-independent dimerization on the cell surface. In addition, we showed that a mutation in a putative Ca 2ϩ -binding site of the ...

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Section: Discussionmentioning

confidence: 99%

Mechanism of Activation of the ret Proto-oncogene by Multiple Endocrine Neoplasia 2A Mutations

Asai

Iwashita

Matsuyama

et al. 1995

Molecular and Cellular Biology

333

224

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“…Furthermore, a segment of 35 amino acids, termed the juxtamembrane (JX) domain, separates the membrane spanning domain from the ®rst tyrosine kinase (K1) domain. Through two of the amino acid substitutions in the extracellular domain and the replacement of the C terminus, the vFms molecule is thought to have gained biochemical properties that are observed with the c-Fms protein only transiently upon binding to M-CSF (Woolford et al, 1988;Roussel et al, 1988). Activation of the tyrosine kinase leads to autophosphorylation of the cytoplasmic domain of the Fms molecule at multiple sites.…”

Section: Introductionmentioning

confidence: 99%

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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“…Since alterations in the ligand-binding region of colony stimulating factor receptor (CSF-1R) has been documented to induce cellular transformation (Roussel et al, 1988) we initially sought to investigate the biological e ects of di erential deletions within the ligand binding domain of the aPDGFR. NIH3T3 cells were transfected with expression vectors coding for wild type aPDGFR (aRWT) and several receptor mutants lacking the individual Ig-like loop 1, 2 and 3 of the aPDGFR designated aR D49 ± 100 , aR D150 ± 189 and aR D235 ± 290 , respectively.…”

Section: Resultsmentioning

confidence: 99%

“…For example, deletion or mutation within the extracellular ligand-binding domains of v-ErbB, v-Kit or v-Fms results in constitutive activation of receptor tyrosine kinase activity (Roussel et al, 1988;Woolford et al, 1988). Another mechanism leading to constitutive activation of a receptor tyrosine kinase is exempli®ed by the Val to Glu mutation in the Erb2 transmembrane domain (Bargmann et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic activation of the αPDGFR defines a domain that negatively regulates receptor dimerization

Uren

Karçaaltıncaba

et al. 1997

Oncogene

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The a platelet derived growth factor receptor (aPDGFR) extracellular Immunoglobulin (Ig) like domains 1 ± 3 contain major determinants for ligand interaction. We now report that a deletion of Ig-like loop 3, but not Iglike loop 1 or 2, of the aPDGFR causes ligandindependent transformation in NIH3T3 cells. Biochemical analyses of aPDGFR mutants lacking Ig-like loop 3 indicate that cellular transformation is mediated by ligand-independent activation of the aPDGFR tyrosine kinase activity as determined by receptor autophosphorylation both in vivo and in vitro. Moreover, crosslinking analysis of aPDGFR mutants expressed ectopically in NIH3T3 cells indicate that deletion within extracellular domain 3 leads to ligand-independent receptor dimerization. All of these ®ndings suggest that the Ig-like loop 3 of the aPDGFR contains the major determinants which inhibit receptor dimerization in the quiescent cells and that the ligand binding induces receptor activation by neutralizing the inhibitory e ect of this domain.

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A point mutation in the extracellular domain of the human CSF-1 receptor (c-fms proto-oncogene product) activates its transforming potential

Cited by 240 publications

References 31 publications

Mechanism of Activation of the ret Proto-oncogene by Multiple Endocrine Neoplasia 2A Mutations

Mechanism of Activation of the ret Proto-oncogene by Multiple Endocrine Neoplasia 2A Mutations

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

Oncogenic activation of the αPDGFR defines a domain that negatively regulates receptor dimerization

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