PubMed · 15821459
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Dolores J Lamb, Lixin Zhang, Ralph Buttyan. 2005. A problem with a chaperone.. https://doi.org/10.1097/01.ju.0000159654.08981.25
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Tyrosyl phosphorylation, which is controlled by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs), regulates numerous cellular processes. Altered expression and/or mutations in PTKs are linked to many forms of cancer, yet until recently little was known about the roles of PTPs in normal cells or in cancer. Earlier work established that a member of the PTP superfamily, PTEN, is an important tumor suppressor gene. We now know that at least one other PTP, the SH2 domain-containing phosphatase Shp2, is a bona fide oncogene that is mutated in several types of leukemia and hyperactivated by other mechanisms in some solid tumors. Understanding how Shp2 and other PTPs contribute to oncogenesis should provide new insights into pathogenesis and might suggest new targets for anti-neoplastic drugs.
Janus kinase 2 (Jak2) associates with cytokine receptors and is essential for signal transduction by mediating tyrosine phosphorylation. Kinase activity is regulated by a series of interactions beginning with the requirement to bind to specific domains in receptors, suppression of activation by the pseudokinase domain, and the requirement for phosphorylation within the activation loop. Recent studies have implicated de-regulation of Jak2 kinase activity by chromosomal translocations in hematopoietic tumors and mutations within the pseudokinase domain in a spectrum of myeloproliferative diseases.
Transcription factors comprise a high proportion of the proteins with dysregulated expression or altered activity in cancer cells. In recent years, great progress has been made in elucidating crucial pathways in leukemogenesis, partially by identifying key transcription factors that are normally indispensable for hematopoiesis but which are often associated with malignant transformation when functioning improperly. The significance of transcription factors is highlighted by the multiple mechanisms used by leukemic cells to abrogate their normal activity. Delineating these mechanisms can benefit the diagnosis and treatment of hematological malignancies and might also be applicable to certain solid tumors.