SHORT COMMUNICATION Chromosomal
Localization of FfJ4, a Novel Receptor-Type Tyrosine Kinase Gene
FRANCK GALLAND, * AibA KARAMYSHEVA, *,’ MARIE-GENEVIEVE MATTEI, t OLIVIER ROSNET,* SYLVIE MARCHETTO,* AND DANIEL BIRNBAUM**~ *Laboratory
of Molecular Oncology, U. 179 INSERM, 27 Blvd. Lei’Roure, 13009 Marseille, France; and tlJ.242 INSERM, Hopital d’enfants de La Timone, Blvd. J. Moulin, 13385 Marseille Cedex 5, France Received
October
7, 1991;
revised
January
13, 1992
A new human gene encoding a putative receptor-type tyrosine kinase (RTK) was isolated by screening a placenta cDNA library with a mouse Flt3 probe. The deduced amino acid sequence of the intracellular region of the molecule showed that it was strongly related to the FLTl and KDR/FLKl gene products and to a lesser degree to members of the class III RTKs: FMS/CSFlR, PDGFRA/B, KIT, and FLT3. The gene was named FLT4. Cosmid clones of the mouse Flt4 gene were isolated. The human gene was localized to bands q34-q35 of chromosome 5, i.e., slightly telomeric to the CSFlR/ PDGFRB tandem of genes, and the mouse homolog to chromosome 11, region A5-Bl . o 1992 Academic PWS, IUC.
Receptor-type tyrosine kinases (RTKs) constitute a large family of molecules, which are divided into several classesbased on their sequence similarities. At least two classes of RTKs are characterized by an extracellular (EC) region composed of repeated immunoglobulin-like domains (IgDs) and a “kinase insert” (KI) interrupting the intracellular (IC) catalytic domain. Proteins with three IgDs are receptors for members of the FGF family. Class III RTKs are characterized by five IgDs and include PDGFRA/B, FMS/CSFlR, KIT (Xi), and the receptor encoded by the FLT3 gene (11,12), also known as FLK2 (9). In addition, two RTKs that comprise seven IgDs are known. They are encoded by the FLTl (13) and KDR/FLKl (8, 14) genes. The RTKs have evolved to serve multiple major functions related to cell growth and differentiation during embryogenesis and adult life, as exemplified by the defects of spontaneous mouse mutants with mutations in the above-mentioned receptors or in their ligands. Several genes from the IgD-RTK classesare grouped in clusters in the mammalian genome. In human, one cluster on chromosome 4 includes KIT and PDGFRA (5, 16). In addition, KDR maps on human chromosome 4 (14), while its mouse counterpart, Flkl, is linked to Pdgfra and Kit (8). A second cluster is found on human chromosome 13 and comprises FLTl and FLT3 (12,17). ’ Permanent address: Cancer Research Center, Institute genesis, Kashirskoye shosse, 24, Moscow 115478, Russia. ’ To whom correspondence should be addressed.
of Carcino-
FIG. 1. Comparison of the amino acid sequences of the putative transmembrane and the intracellular portions of human FLT4 and three other related RTKs. Sequences are aligned to allow comparison, with gaps (shown as dashes) introduced to maximize the alignment. The starts of the corresponding regions (TM, transmembrane domain; TKl, tyrosine kinase 1; KI, kinase insert; TK2, tyrosine kinase 2; C-TER: C-terminal region) are indicated above the sequences. Boundaries of the domains were determined according to Hanks et al. (5). Amino acid sequences for FLTl, KDR, and FMS were taken from Shibuya et al. (13), Terman et al. (14), and Coussens et al. (2), respectively. The partial sequence of the mouse Flt4 gene product (designated Mu-FLT4) is shown above the corresponding part of human FLT4. Sequence similarities are as follows: FLT4 vs FLTl, 61.6%; FLT4 vs KDR, 62.5%. Identical amino acids in the four molecules are indicated by asterisks. 13, 475-478
GENOMICS
475
oma-7543/92
Copyright All
rights
0
1992 of reproduction
by
Academic in any
form
(19%) $5.00
Press, Inc. reserved.
476
SHORT
COMMUNICATION
FIG. 2. Localization of the human FLT4 gene to chromosome 5. (Left) Two partial human metaphases showing the specific site of hybridization to chromosome 5. Top: Arrowheads indicate silver grains on Giemsa-stained chromosomes, after autoradiography. Bottom: Chromosomes with silver grains were subsequently identified by R-banding (FPG technique). (Right) Idiogram of the human G-banded chromosome illustrating the distribution of labeled sites for the pHP3L probe.
5
t 11 1. t
FIG. 3. Localization of the mouse Flt4 gene to chromosome 11. (Left) hybridization to chromosome 11. Top: Arrowheads indicate silver grains Chromosomes with silver grains were subsequently identified by R-banding. the distribution of labeled sites on chromosome 11 for the pKA-3 probe.
Two partial WMP mouse metaphases, showing the specific site of on Giemsa-stained chromosomes, after autoradiography. Bottom: (Right) Diagram of WMP mouse Rb(l;ll) chromosome, indicating
SHORT
COMMUNICATION
A third cluster, located at 5q33-34, comprises the closely linked CSFlR and PDGFRB genes (10). Clustering is also observed in mouse. We report here the isolation, partial sequence, and chromosomal localization of FLT4, a gene related to FLTl and KDR/FLKl. A human placenta Xgtll cDNA library (Clontech, Palo Alto, CA) was screened with a murine FZt3 cDNA probe consisting of a l.O-kb cDNA fragment called FT5 (11,12) and corresponding to a portion of the IC region of the FLT3 protein. Among several clones, one nonFLT3 cDNA clone (called HP3), 1.5 kb long, was obtained. Nucleotide sequencing of HP3 showed that it corresponded to a new gene having extensive sequence similarities to the RTK genes. Several FLT4 cDNA clones were subsequently obtained by repeated screenings of the library using a FLT4 probe named HP3L, which consisted of a 0.35kb EcoRI cDNA fragment. A strong similarity (62%) was observed between the amino acid sequences deduced from the nucleotide sequence of the FLT4 clones and the corresponding regions of the FLTl and KDR/FLKl gene products (13, 14). This is shown in Fig. 1. The FLT4, FLTl, and KDR/FLKl gene products are more related to each other than to members of the CSFlR/KIT/PDGFR family and thus tentatively identify a separate class of RTKs. We cloned part of the mouse Flt4 from a cosmid library of embryonic stem cells by screening with a combination of human FLT4 cDNA probes, HP3U and 71ml (1.16-kb EcoRI and 0.4-kb EcoRI-Sal1 fragments, respectively). The nucleotide sequence of the pKA-3 subclone, a subclone of a 0.5-kb genomic PuuII-EcoRI insert derived from a cosmid clone, showed that it contained part of the mouse Flt4 gene. The amino acid sequence deduced from this analysis is shown in Fig. 1 for comparison. It corresponds to a portion of the tyrosine kinase domain that, in the CSFlR, is encoded by exon 18 (4). We determined the chromosomal localization of the human FLT4 gene by in situ hybridization carried out on chromosome preparations obtained from phytohemagglutinin-stimulated lymphocytes. Cells were cultured for 72 h with 5-bromo-deoxyuridine added for the final 6 h of culture. The pHP3L plasmid, containing a 0.35-kb insert of human FLT4 in a Bluescript vector, was 3H-labeled by nick-translation and hybridized to final concentrations of 3 to 25 rig/ml, as previously described (7). After coating with nuclear track emulsion (Kodak NTBB), the slides were exposed for 10 to 14 days. Chromosome spreads were stained with buffered Giemsa solution and metaphases photographed. R-banding was then performed by the FPG method (l), and metaphases were rephotographed before analysis. In the 150 metaphase cells examined, 412 silver grains were associated with chromosomes, and 51 of these (12.3%) were located on chromosome 5. The distribution of the grains on this chromosome was not random: 62.7% of them mapped to the q34-q35 region of chromosome 5, with a maximum in the 5q35 band. The results shown in Fig. 2 suggest
477
that the localization of the FLT4 gene is the 5q35 band, i.e., the distal band of the chromosome 5 long arm. Next, in situ hybridization experiments were carried out on mouse chromosomes from concanavalin A-stimulated lymphocytes from a WMP mouse in which all the autosomes except 19 are Robertsonian translocations, using the pKA-3 plasmid as a probe. In the 100 metaphase cells examined, 267 silver grains were associated with chromosomes, and 51 of these (19.1%) were located on chromosome 11. The distribution of the grains on this chromosome was not random: 68.6% of them mapped to the A5-Bl region of chromosome 11. These results, shown in Fig. 3, allowed us to map the mouse Flt4 gene to the llA5-llB1 region of the murine genome. We have identified and partially cloned a gene encoding a protein strongly related to the FLTl and KDR/ FLKl gene products. The FLTl, KDR/FLKl, and FLT4 genes are on separate chromosomes and clustered with genes of other RTK classes. FLT4 is part of a group including the tandem CSFIRIPDGFRB and the FGFR4 gene (3, 10). Translocations observed in lymphomas involve the 5q35 region and the status of FLT4 in lymphoma cells carrying this translocation will be interesting to study. In mouse, the tandem Csflr/Pdgfrb is located on chromosome 18, but the Fit4 gene maps on a distinct chromosome, namely, chromosome 11. ACKNOWLEDGMENTS We are grateful to Patrice Dubreuil for the gift of the ES DNA, to Francois Coulier and Odile deLapeyriere for helpful comments, and to Robert Rottapel for critical reading of the manuscript. This work was supported by INSERM and grants from the FNCLCC and the Comite Departemental des Bouches-du-Rhone de la Ligue contre le Cancer.
REFERENCES 1.
Camargo, M., and Cervenka, tion of human chromosomes. model. Am. J. Hum. Genet.
2.
Coussens, L., Van Beveren, C., Smith, D., Chen, E., Mitchell, R., Isacke, C., Verma, I., and Ullrich, A. (1986). Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature 320: 277-280.
3.
Eerola, E., Partanen, J., Cannizzaro, K., and Alitalo, K. (1992). Localization of fibroblast growth factor receptor-4 gene to chromosome 5q33-qter. Genes Chrom. Cancer, in press. Hampe, A., Shamoon, B. M., Gobet, M., Sherr, C., and Galibert, F. (1989). Nucleotide sequence and structural organization of the human FMS proto-oncogene. Oncogene Res. 4: 9-17.
4.
5.
6.
7.
8.
J. (1982). Patterns of DNA replicaII. Replication map and replication 34: 757-780.
Hanks, S., Quinn, A. M., and Hunter, T. (1988). The protein kinase family: Conserved features and deduced phylogeny of the catalytic domains. Science 241: 42-52. Matsui, T., Heidaran, M., Miki, T., Popescu, N., LaRochelle, W., Kraus, M., Pierce, J., and Aaronson, S. (1989). Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes. Science 243: 800-803. Mattei, M. G., Philip, N., Passage, E., Moisan, J. P., Mandel, J. L., and Mattei, J. F. (1985). DNA nrobe localization at 18~113 band by in situ hybridization and identification of a small supernumerary chromosome. Hum. Genet. 69: 268-271. Matthews, W., Jordan, C., Gavin, M., Jenkins, N., Copeland, N., and Lemischka, I. (1991). A receptor tyrosine kinase cDNA iso-
478
SHORT
lated from a population of enriched primitive hematopoietic and exhibiting close genetic linkage to c-kit. Proc. Natl. Sci. USA. 88: 9026-9030. 9.
10.
COMMUNICATION
cells Acad.
Matthews, W., Jordan, C., Wiegand, G., Pardoll, D., and Lemischka, I. (1991). A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 65: 1143-1152. Roberts, M., Look, T., Roussel, M., and Sherr, C. (1988). Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes. Cell 55: 655-661.
11.
Rosnet, O., Marchetto, S., delapeyriere, O., and Birnbaum, (1991). Murine FZt3, a gene encoding a novel tyrosine kinase ceptor of the PDGFR/CSFlR family. Oncogene 6: 1641-1650.
12.
Rosnet, O., Mattei, M. G., Marchetto, S., and Birnbaum, D. (1991). Isolation and chromosomal localization of a novel FMSlike tyrosine kinase gene. Genomics 9: 380-385.
13.
Shibuya,
M.,
Yamaguchi,
S., Yamane,
A., Ikeda,
T.,
Tojo,
Matsushime, H., and Sato, M. (1990). Nucleotide sequence expression of a novel human receptor-type tyrosine kinase (fit) closely related to the fms family. Oncogene 5: 519-524. 14.
15.
Terman, B., Carrion, M., Kovacs, E., Rasmussen, B., Eddy, R., and Shows, T. (1991). Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6: 1677-1683. Ullrich, A., and Schlessinger, J. (1990). Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203-212.
16.
Yarden, Y., Kuang, W. J., Yang-Feng, T., Coussens, L., Munemitsu, S., Dull, T., Chen, E., Schlessinger, J., Francke, U., and Ullrich, A. (1987). Human proto-oncogene c-kit: A new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 6: 3341-3351.
17.
Yoshida, M., Satoh, H., Matsushime, H., Shibuya, M., and Sasaki, M. (1987). Two ros-related protooncogenes, c-ros-1 and flt, are regionally mapped on human chromosomes 6q22 and 13q12, respectively. Cytogenet. Cell Genet. 46: 724.
D. re-
A.,
and gene
Localization of FfJ4, a Novel Receptor-Type Tyrosine Kinase Gene
FRANCK GALLAND, * AibA KARAMYSHEVA, *,’ MARIE-GENEVIEVE MATTEI, t OLIVIER ROSNET,* SYLVIE MARCHETTO,* AND DANIEL BIRNBAUM**~ *Laboratory
of Molecular Oncology, U. 179 INSERM, 27 Blvd. Lei’Roure, 13009 Marseille, France; and tlJ.242 INSERM, Hopital d’enfants de La Timone, Blvd. J. Moulin, 13385 Marseille Cedex 5, France Received
October
7, 1991;
revised
January
13, 1992
A new human gene encoding a putative receptor-type tyrosine kinase (RTK) was isolated by screening a placenta cDNA library with a mouse Flt3 probe. The deduced amino acid sequence of the intracellular region of the molecule showed that it was strongly related to the FLTl and KDR/FLKl gene products and to a lesser degree to members of the class III RTKs: FMS/CSFlR, PDGFRA/B, KIT, and FLT3. The gene was named FLT4. Cosmid clones of the mouse Flt4 gene were isolated. The human gene was localized to bands q34-q35 of chromosome 5, i.e., slightly telomeric to the CSFlR/ PDGFRB tandem of genes, and the mouse homolog to chromosome 11, region A5-Bl . o 1992 Academic PWS, IUC.
Receptor-type tyrosine kinases (RTKs) constitute a large family of molecules, which are divided into several classesbased on their sequence similarities. At least two classes of RTKs are characterized by an extracellular (EC) region composed of repeated immunoglobulin-like domains (IgDs) and a “kinase insert” (KI) interrupting the intracellular (IC) catalytic domain. Proteins with three IgDs are receptors for members of the FGF family. Class III RTKs are characterized by five IgDs and include PDGFRA/B, FMS/CSFlR, KIT (Xi), and the receptor encoded by the FLT3 gene (11,12), also known as FLK2 (9). In addition, two RTKs that comprise seven IgDs are known. They are encoded by the FLTl (13) and KDR/FLKl (8, 14) genes. The RTKs have evolved to serve multiple major functions related to cell growth and differentiation during embryogenesis and adult life, as exemplified by the defects of spontaneous mouse mutants with mutations in the above-mentioned receptors or in their ligands. Several genes from the IgD-RTK classesare grouped in clusters in the mammalian genome. In human, one cluster on chromosome 4 includes KIT and PDGFRA (5, 16). In addition, KDR maps on human chromosome 4 (14), while its mouse counterpart, Flkl, is linked to Pdgfra and Kit (8). A second cluster is found on human chromosome 13 and comprises FLTl and FLT3 (12,17). ’ Permanent address: Cancer Research Center, Institute genesis, Kashirskoye shosse, 24, Moscow 115478, Russia. ’ To whom correspondence should be addressed.
of Carcino-
FIG. 1. Comparison of the amino acid sequences of the putative transmembrane and the intracellular portions of human FLT4 and three other related RTKs. Sequences are aligned to allow comparison, with gaps (shown as dashes) introduced to maximize the alignment. The starts of the corresponding regions (TM, transmembrane domain; TKl, tyrosine kinase 1; KI, kinase insert; TK2, tyrosine kinase 2; C-TER: C-terminal region) are indicated above the sequences. Boundaries of the domains were determined according to Hanks et al. (5). Amino acid sequences for FLTl, KDR, and FMS were taken from Shibuya et al. (13), Terman et al. (14), and Coussens et al. (2), respectively. The partial sequence of the mouse Flt4 gene product (designated Mu-FLT4) is shown above the corresponding part of human FLT4. Sequence similarities are as follows: FLT4 vs FLTl, 61.6%; FLT4 vs KDR, 62.5%. Identical amino acids in the four molecules are indicated by asterisks. 13, 475-478
GENOMICS
475
oma-7543/92
Copyright All
rights
0
1992 of reproduction
by
Academic in any
form
(19%) $5.00
Press, Inc. reserved.
476
SHORT
COMMUNICATION
FIG. 2. Localization of the human FLT4 gene to chromosome 5. (Left) Two partial human metaphases showing the specific site of hybridization to chromosome 5. Top: Arrowheads indicate silver grains on Giemsa-stained chromosomes, after autoradiography. Bottom: Chromosomes with silver grains were subsequently identified by R-banding (FPG technique). (Right) Idiogram of the human G-banded chromosome illustrating the distribution of labeled sites for the pHP3L probe.
5
t 11 1. t
FIG. 3. Localization of the mouse Flt4 gene to chromosome 11. (Left) hybridization to chromosome 11. Top: Arrowheads indicate silver grains Chromosomes with silver grains were subsequently identified by R-banding. the distribution of labeled sites on chromosome 11 for the pKA-3 probe.
Two partial WMP mouse metaphases, showing the specific site of on Giemsa-stained chromosomes, after autoradiography. Bottom: (Right) Diagram of WMP mouse Rb(l;ll) chromosome, indicating
SHORT
COMMUNICATION
A third cluster, located at 5q33-34, comprises the closely linked CSFlR and PDGFRB genes (10). Clustering is also observed in mouse. We report here the isolation, partial sequence, and chromosomal localization of FLT4, a gene related to FLTl and KDR/FLKl. A human placenta Xgtll cDNA library (Clontech, Palo Alto, CA) was screened with a murine FZt3 cDNA probe consisting of a l.O-kb cDNA fragment called FT5 (11,12) and corresponding to a portion of the IC region of the FLT3 protein. Among several clones, one nonFLT3 cDNA clone (called HP3), 1.5 kb long, was obtained. Nucleotide sequencing of HP3 showed that it corresponded to a new gene having extensive sequence similarities to the RTK genes. Several FLT4 cDNA clones were subsequently obtained by repeated screenings of the library using a FLT4 probe named HP3L, which consisted of a 0.35kb EcoRI cDNA fragment. A strong similarity (62%) was observed between the amino acid sequences deduced from the nucleotide sequence of the FLT4 clones and the corresponding regions of the FLTl and KDR/FLKl gene products (13, 14). This is shown in Fig. 1. The FLT4, FLTl, and KDR/FLKl gene products are more related to each other than to members of the CSFlR/KIT/PDGFR family and thus tentatively identify a separate class of RTKs. We cloned part of the mouse Flt4 from a cosmid library of embryonic stem cells by screening with a combination of human FLT4 cDNA probes, HP3U and 71ml (1.16-kb EcoRI and 0.4-kb EcoRI-Sal1 fragments, respectively). The nucleotide sequence of the pKA-3 subclone, a subclone of a 0.5-kb genomic PuuII-EcoRI insert derived from a cosmid clone, showed that it contained part of the mouse Flt4 gene. The amino acid sequence deduced from this analysis is shown in Fig. 1 for comparison. It corresponds to a portion of the tyrosine kinase domain that, in the CSFlR, is encoded by exon 18 (4). We determined the chromosomal localization of the human FLT4 gene by in situ hybridization carried out on chromosome preparations obtained from phytohemagglutinin-stimulated lymphocytes. Cells were cultured for 72 h with 5-bromo-deoxyuridine added for the final 6 h of culture. The pHP3L plasmid, containing a 0.35-kb insert of human FLT4 in a Bluescript vector, was 3H-labeled by nick-translation and hybridized to final concentrations of 3 to 25 rig/ml, as previously described (7). After coating with nuclear track emulsion (Kodak NTBB), the slides were exposed for 10 to 14 days. Chromosome spreads were stained with buffered Giemsa solution and metaphases photographed. R-banding was then performed by the FPG method (l), and metaphases were rephotographed before analysis. In the 150 metaphase cells examined, 412 silver grains were associated with chromosomes, and 51 of these (12.3%) were located on chromosome 5. The distribution of the grains on this chromosome was not random: 62.7% of them mapped to the q34-q35 region of chromosome 5, with a maximum in the 5q35 band. The results shown in Fig. 2 suggest
477
that the localization of the FLT4 gene is the 5q35 band, i.e., the distal band of the chromosome 5 long arm. Next, in situ hybridization experiments were carried out on mouse chromosomes from concanavalin A-stimulated lymphocytes from a WMP mouse in which all the autosomes except 19 are Robertsonian translocations, using the pKA-3 plasmid as a probe. In the 100 metaphase cells examined, 267 silver grains were associated with chromosomes, and 51 of these (19.1%) were located on chromosome 11. The distribution of the grains on this chromosome was not random: 68.6% of them mapped to the A5-Bl region of chromosome 11. These results, shown in Fig. 3, allowed us to map the mouse Flt4 gene to the llA5-llB1 region of the murine genome. We have identified and partially cloned a gene encoding a protein strongly related to the FLTl and KDR/ FLKl gene products. The FLTl, KDR/FLKl, and FLT4 genes are on separate chromosomes and clustered with genes of other RTK classes. FLT4 is part of a group including the tandem CSFIRIPDGFRB and the FGFR4 gene (3, 10). Translocations observed in lymphomas involve the 5q35 region and the status of FLT4 in lymphoma cells carrying this translocation will be interesting to study. In mouse, the tandem Csflr/Pdgfrb is located on chromosome 18, but the Fit4 gene maps on a distinct chromosome, namely, chromosome 11. ACKNOWLEDGMENTS We are grateful to Patrice Dubreuil for the gift of the ES DNA, to Francois Coulier and Odile deLapeyriere for helpful comments, and to Robert Rottapel for critical reading of the manuscript. This work was supported by INSERM and grants from the FNCLCC and the Comite Departemental des Bouches-du-Rhone de la Ligue contre le Cancer.
REFERENCES 1.
Camargo, M., and Cervenka, tion of human chromosomes. model. Am. J. Hum. Genet.
2.
Coussens, L., Van Beveren, C., Smith, D., Chen, E., Mitchell, R., Isacke, C., Verma, I., and Ullrich, A. (1986). Structural alteration of viral homologue of receptor proto-oncogene fms at carboxyl terminus. Nature 320: 277-280.
3.
Eerola, E., Partanen, J., Cannizzaro, K., and Alitalo, K. (1992). Localization of fibroblast growth factor receptor-4 gene to chromosome 5q33-qter. Genes Chrom. Cancer, in press. Hampe, A., Shamoon, B. M., Gobet, M., Sherr, C., and Galibert, F. (1989). Nucleotide sequence and structural organization of the human FMS proto-oncogene. Oncogene Res. 4: 9-17.
4.
5.
6.
7.
8.
J. (1982). Patterns of DNA replicaII. Replication map and replication 34: 757-780.
Hanks, S., Quinn, A. M., and Hunter, T. (1988). The protein kinase family: Conserved features and deduced phylogeny of the catalytic domains. Science 241: 42-52. Matsui, T., Heidaran, M., Miki, T., Popescu, N., LaRochelle, W., Kraus, M., Pierce, J., and Aaronson, S. (1989). Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes. Science 243: 800-803. Mattei, M. G., Philip, N., Passage, E., Moisan, J. P., Mandel, J. L., and Mattei, J. F. (1985). DNA nrobe localization at 18~113 band by in situ hybridization and identification of a small supernumerary chromosome. Hum. Genet. 69: 268-271. Matthews, W., Jordan, C., Gavin, M., Jenkins, N., Copeland, N., and Lemischka, I. (1991). A receptor tyrosine kinase cDNA iso-
478
SHORT
lated from a population of enriched primitive hematopoietic and exhibiting close genetic linkage to c-kit. Proc. Natl. Sci. USA. 88: 9026-9030. 9.
10.
COMMUNICATION
cells Acad.
Matthews, W., Jordan, C., Wiegand, G., Pardoll, D., and Lemischka, I. (1991). A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 65: 1143-1152. Roberts, M., Look, T., Roussel, M., and Sherr, C. (1988). Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes. Cell 55: 655-661.
11.
Rosnet, O., Marchetto, S., delapeyriere, O., and Birnbaum, (1991). Murine FZt3, a gene encoding a novel tyrosine kinase ceptor of the PDGFR/CSFlR family. Oncogene 6: 1641-1650.
12.
Rosnet, O., Mattei, M. G., Marchetto, S., and Birnbaum, D. (1991). Isolation and chromosomal localization of a novel FMSlike tyrosine kinase gene. Genomics 9: 380-385.
13.
Shibuya,
M.,
Yamaguchi,
S., Yamane,
A., Ikeda,
T.,
Tojo,
Matsushime, H., and Sato, M. (1990). Nucleotide sequence expression of a novel human receptor-type tyrosine kinase (fit) closely related to the fms family. Oncogene 5: 519-524. 14.
15.
Terman, B., Carrion, M., Kovacs, E., Rasmussen, B., Eddy, R., and Shows, T. (1991). Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6: 1677-1683. Ullrich, A., and Schlessinger, J. (1990). Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203-212.
16.
Yarden, Y., Kuang, W. J., Yang-Feng, T., Coussens, L., Munemitsu, S., Dull, T., Chen, E., Schlessinger, J., Francke, U., and Ullrich, A. (1987). Human proto-oncogene c-kit: A new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 6: 3341-3351.
17.
Yoshida, M., Satoh, H., Matsushime, H., Shibuya, M., and Sasaki, M. (1987). Two ros-related protooncogenes, c-ros-1 and flt, are regionally mapped on human chromosomes 6q22 and 13q12, respectively. Cytogenet. Cell Genet. 46: 724.
D. re-
A.,
and gene
