Mechanism of activation of the human trk oncogene.

The human trk oncogene was generated by a genetic rearrangement that replaced the extracellular domain of the normal trk tyrosine kinase receptor by sequences coding for the 221 amino-terminal residues of a nonmuscle tropomyosin. Molecular dissection of a cDNA clone of the trk oncogene indicated that both the tropomyosin and tyrosine kinase domains were required for proper transforming activity. Replacement of nonmuscle tropomyosin sequences with those of other tropomyosin isoforms had no deleterious effect. However, when tropomyosin sequences were replaced with those of another cytoskeletal gene, such as beta-actin or beta-globin, transforming activity was completely abolished. These results illustrate the important role of tropomyosin sequences in endowing the trk kinase with transforming properties. Functionally unrelated subdomains of the tropomyosin molecule were equally efficient in activating the trk gene. Moreover, the transforming activity of the trk oncogene was not affected when its subcellular localization was drastically altered. Therefore, tropomyosin sequences are likely to contribute to the malignant activation of the trk oncogene not by facilitating its interaction with defined cytoskeletal structures as initially suspected, but by allowing its kinase domain to fold into a constitutively active configuration.

[1]  M. Barbacid,et al.  Molecular and biochemical characterization of the human trk proto-oncogene , 1989, Molecular and cellular biology.

[2]  M. Barbacid,et al.  Frequent generation of oncogenes by in vitro recombination of TRK protooncogene sequences. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[3]  C. W. Smith,et al.  The rat alpha-tropomyosin gene generates a minimum of six different mRNAs coding for striated, smooth, and nonmuscle isoforms by alternative splicing , 1988, Molecular and cellular biology.

[4]  B. Groner,et al.  Activation of the receptor kinase domain of the trk oncogene by recombination with two different cellular sequences. , 1988, The EMBO journal.

[5]  M. Barbacid,et al.  Identification and biochemical characterization of p70TRK, product of the human TRK oncogene. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. J. van de Vijver,et al.  Amplification of the neu (c-erbB-2) oncogene in human mammmary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene , 1987, Molecular and cellular biology.

[7]  M. Kraus,et al.  Overexpression of the EGF receptor‐related proto‐oncogene erbB‐2 in human mammary tumor cell lines by different molecular mechanisms. , 1987, The EMBO journal.

[8]  M. Greaves,et al.  A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia positive acute lymphoblastic leukaemia , 1987, Nature.

[9]  R. Kurzrock,et al.  A novel c-abl protein product in Philadelphia-positive acute lymphoblastic leukaemia , 1987, Nature.

[10]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[11]  R. Jove,et al.  Cell transformation by the viral src oncogene. , 1987, Annual review of cell biology.

[12]  M. Barbacid.  ras genes. , 1987, Annual review of biochemistry.

[13]  M. Barbacid,et al.  Molecular characterization of the human trk oncogene. , 1986, Cold Spring Harbor symposia on quantitative biology.

[14]  M. Barbacid,et al.  A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences , 1986, Nature.

[15]  F. Walsh,et al.  A muscle-type tropomyosin in human fibroblasts: evidence for expression by an alternative RNA splicing mechanism. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[16]  O. Witte,et al.  Detection of c-abl tyrosine kinase activity in vitro permits direct comparison of normal and altered abl gene products , 1985, Molecular and cellular biology.

[17]  E. Canaani,et al.  Fused transcript of abl and bcr genes in chronic myelogenous leukaemia , 1985, Nature.

[18]  O. Witte,et al.  Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Hermona Soreq,et al.  Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin , 1985, Nature.

[20]  Thomas A. Kunkel,et al.  Rapid and efficient site-specific mutagenesis without phenotypic selection. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[21]  P. Seeburg,et al.  Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells , 1984, Nature.

[22]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[23]  S. Hughes,et al.  The nucleotide sequence of the chick cytoplasmic β-actin gene , 1983 .

[24]  J. Stephenson,et al.  Localization of the c-abl oncogene adjacent to a translocation break point in chronic myelocytic leukaemia , 1983, Nature.

[25]  M. Barbacid,et al.  Oncogenes in solid human tumours , 1982, Nature.

[26]  M. Barbacid,et al.  Gene products of McDonough feline sarcoma virus have an in vitro-associated protein kinase that phosphorylates tyrosine residues: lack of detection of this enzymatic activity in vivo , 1981, Journal of virology.

[27]  T. Shenk,et al.  The sequence 5′-AAUAAA-3′ forms part of the recognition site for polyadenylation of late SV40 mRNAs , 1981, Cell.

[28]  M. Barbacid,et al.  Origin and functional properties of the major gene product of the Snyder-Theilen strain of feline sarcoma virus. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[29]  L. Enquist,et al.  Nucleotide sequences of integrated Moloney sarcoma provirus long terminal repeats and their host and viral junctions. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[30]  S. Weissman,et al.  Human beta-globin messenger RNA. I. Nucleotide sequences derived from complementary RNA. , 1977, The Journal of biological chemistry.

[31]  A. van der Eb,et al.  A new technique for the assay of infectivity of human adenovirus 5 DNA. , 1973, Virology.

[32]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.