The history of tyrosine kinase oncogenes can be traced to 1911 when Peyton Rous, of the Rockefeller Institute, demonstrated that a chicken tumor could be wx transplanted using a cell-free filtrate 1. However, it was not until more recent advances in molecular biology that it was recognized that the transforming activity of the Rous sarcoma virus is due to the wx presence of the SRC oncogene in its genome 2. In 1976, Drs. Varmus and Bishop published the finding that the SRC oncogene in the virus was not a true viral gene but instead was a normal cellular gene which the virus had acquired during replication in the wx host cell 3. It took several more years to determine that the SRC oncogene possesses an intrinsic kinase Ž activity that is specific for tyrosine residues rew x. viewed in 4. However, the transforming viral version of the SRC oncogene, v-SRC, is mutated and constitutively active as compared to its tightly regulated cellular homologue, c-SRC. Since the discovery of the SRC oncogene as a protein tyrosine kinase, numerous tyrosine kinases have been found, and now number over 100. Tyrosine kinases act to transfer phosphate from ATP to tyrosine residues on specific cellular proteins. The list of tyrosine kinases includes proteins that are involved in pathways that regulate cellular growth, activation, and differentiation. Despite the essential contribution of tyrosine kinase oncogenes to our current understanding of a variety of cellular signaling pathways, and their historical importance to the field of tumor Ž w x. biology reviewed in 5, only a limited role for tyrosine kinases in human cancers has been identified. In this article, the mechanisms by which protein tyrosine kinases may participate in malignant transformation and the tyrosine kinases which are known to play prominent roles in human cancer will be reviewed.

Cancer is thought to reflect a multi-step process, resulting from an accumulation of inherited andror acquired defects in genes involved in the positive or negative regulation of cell proliferation and survival. Activation or inactivation of as many as four or five different genes may be required for the development of a clinically recognizable human cancer. Some abnormalities may be necessary for the development of neoplasia, but few are sufficient. Tyrosine kinases can be involved in any of several steps of neoplastic development and progression. Tyrosine kinases can play major, etiologic roles in the initiation of malignancy, and several examples from human disease will be discussed. Alternatively, tyrosine kinases may contribute to the uncontrolled proliferation of cancer cells, tumor progression, and development of metastatic disease, without directly initiating the neoplastic process. Several examples of this type of involvement of tyrosine kinases in cancer will be reviewed, and the difficulties involved in elucidating the role of tyrosine kinases in human malignancies will be discussed.