Nucleotide sequences of feline retroviral oncogenes (v-fes) provide evidence for a family of tyrosine-specific protein kinase genes

104

The nucleotide sequence of the 3' two-thirds of a highly conserved, molecularly cloned human cellular src gene (c-src) has been determined. This region of the c-src gene encodes the tyrosine kinase domain of the cellular src protein (pp60csrc) and corresponds to exons 6 through 12 of the chicken c-src gene, as well as nucleotides 545 to 1542 of the Rous sarcoma virus src gene (v-src). The human c-src sequence is very strongly conserved with respect to both the chicken c-src and the Rous sarcoma virus v-src genes, with nearly 90% nucleotide homology observed in this region. Amino acid sequence conservation in this region is even greater; 98% of the amino acids are conserved between human and chicken c-src. Furthermore, the exon sizes and the locations of the exon-intron boundaries are identical in the human and chicken c-src genes. However, sequences within the introns have not been conserved, and the introns within the human c-src gene are significantly larger than the corresponding introns within the chicken c-src gene. The strong amino acid conservation between the carboxy-terminal two-thirds of pp60`csrc of species as divergent as humans and chickens suggests that this portion of the pp60`csrc protein specifies one or more functional domains that are of great importance to some aspect of normal cellular growth or differentiation.The retroviral oncogenes are derived from normal cellular sequences (proto-oncogenes) which have been acquired from host cells (5). Often these genes have undergone modification during the process of viral transduction and virus propagation, resulting in small changes in nucleotide sequence, insertions, or deletions, or more than one of the above, within the coding or control sequences of the gene. It is thought that some of these modifications might be involved in imparting an acute transforming ability to the retroviruses that carry these oncogenes (reviewed in reference 4). The Rous sarcoma virus (RSV) src gene (v-src) is one of the most extensively studied retroviral oncogenes. Nucleic acid hybridization studies have shown that a cellular counterpart of v-src is present in the normal cells of all vertebrate species examined (50, 51) as well as in Drosophila melanogaster (46). The chicken c-src gene is expressed at relatively low levels in most cell and tissue types, but mRNA levels have been found to be elevated in macrophages (16), and levels of pp6Oc-src were found to be elevated in neural tissue during development (8, 49). pp6Oc-src possesses a tyrosine kinase activity analogous to that of the v-src protein pp6vsrc (7,33), and recently pp60v-sr' has been shown to possess an inositol phosphorylating activity (53), which may be related to the tyrosine kinase activity.The chicken c-src gene has recently been characterized by molecular cloning and DNA sequencing (35,43,55,56).

Section: Discussionmentioning

confidence: 66%

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confidence: 77%

Human cellular src gene: nucleotide sequence and derived amino acid sequence of the region coding for the carboxy-terminal two-thirds of pp60c-src.

Anderson¹,

Gibbs²,

Tanaka³

et al. 1985

104

“…The products encoded by some identified v-onc genes are associated with tyrosine-specific kinase activity (src, yes, abl, ros, andfes; reviewed in reference 2). Nucleotide sequence analysis (9,26) and measurements of immunological cross-reactivity (1) support the idea that some of these oncogenes (the src family) are evolutionarily related. The recent discovery of a gene that is homologous to v-src and v-abl in Drosophila melanogaster DNA further suggests that these oncogenes may have evolved from a common ancestral gene (14).…”

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confidence: 98%

Chromosomal mapping of murine c-fes and c-src genes.

Blatt¹,

Harper²,

Franchini³

et al. 1984

The murine homologs of two viral oncogenes associated with tyrosine-specific kinase activity have been assigned to different loci in the mouse genome. The segregation of restriction site polymorphisms, as detected by probes that are specific for endogenous c-fes and c-src sequences, was followed in the DNA of recombinant inbred strains. The c-fes gene was mapped to the proximal portion of chromosome 7, very close to the Gpi-1 locus, whereas c-src was linked to the Psp locus on the distal half of chromosome 2.

“…DNA sequence analysis of cloned retroviral genomes suggests that a number of viral oncogenes originally thought to be unrelated were probably derived from a common ancestor gene (19,50). This group of oncogenes is known as the src gene family and it includes the src, fpslfes, yes, ros, fms, abl, erbB, and fgr genes (3).…”

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confidence: 99%

“…This group of oncogenes is known as the src gene family and it includes the src, fpslfes, yes, ros, fms, abl, erbB, and fgr genes (3). The proteins encoded by these genes have a high degree of amino acid sequence homology (9,18,19,25,34,35,39,40,47,50,55,61), and they are associated with tyrosine-specific protein kinase activities (1,2,8,14,15,17,21,24,26,33,37,41,43,57) that are believed to be essential to the mechanism of cell transformation. Viral oncogenes were derived from cellular oncogenes by a process of recombination between viral and cellular sequences.…”

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confidence: 99%

Antipeptide antiserum identifies a widely distributed cellular tyrosine kinase related to but distinct from the c-fps/fes-encoded protein.

Feldman¹,

Tam²,

Hanafusa³

1986

We raised antibodies directed against a synthetic peptide representing an amino acid sequence of the conserved kinase domain of the transforming protein of Fujinami sarcoma virus (FSV) (P140). The antiserum obtained specifically recognized FSV-P140 and its cellular homolog and in addition, it recognized a new cellular protein of 94,000 daltons (NCP94) in avian and mammalian cells. NCP94 was found to be associated with a cyclic nucleotide-independent protein kinase activity that was specific for tyrosine residues. Although NCP94 and FSV-P140 share antigenic determinants, NCP94 is not a cellular homolog of FSV-P140: NCP94 and the previously identified c-fps/fes product were different in their tryptic fingerprints and in their tissue specificities. Thus, the function of NCP94 in normal cells is probably different than that of the c-fps/fes product. NCP94 was expressed in every tissue and cell line that was examined. In chickens, NCP94 levels were highest during embryonic development and NCP94 expression was high in gizz4rd, brain, and spleen throughout embryonic and adult life. The universal expression of NCP94 suggests that this protein may be involved in an essential function of normal cells. NCP94 may be a new ceDlular tyrosine kinase of the src gene family.