RESUMEN
In the middle of the 20th century, animal tumor viruses were heralded as possible models for understanding human cancer. By the mid-1970s, the molecular basis by which tumor viruses transform cells into a malignant state was beginning to emerge as the first viral genomic sequences were reported and the proteins encoded by their transforming genes were identified and characterized. This was a time of great excitement and rapid progress. In 1978, prompted by the discovery from Ray Erikson's group that the Rous sarcoma virus (RSV) v-Src-transforming protein had an associated protein kinase activity specific for threonine, my group at the Salk Institute set out to determine whether the polyomavirus middle T-transforming protein had a similar kinase activity. Here, I describe the experiments that led to the identification of a kinase activity associated with middle T antigen and our serendipitous discovery that this activity was specific for tyrosine in vitro, and how this in turn led to the fortuitous observation that the v-Src-associated kinase activity was also specific for tyrosine. Our finding that v-Src increased the level of phosphotyrosine in cellular proteins in RSV-transformed cells confirmed that v-Src is a tyrosine kinase and transforms cells by phosphorylating proteins on tyrosine. My colleague Bart Sefton and I reported these findings in the March issue of PNAS in 1980. Remarkably, all of the experiments in this paper were accomplished in less than one month.
Asunto(s)
Proteínas Tirosina Quinasas/historia , Historia del Siglo XX , Fosforilación , Proteínas Tirosina Quinasas/metabolismoRESUMEN
We performed a literature search that shed light on the signaling pathways involved in the sorafenib activity as first- or subsequent-line treatment, taking into account its toxicity profile. Sorafenib appears to have better tolerability when compared with other agents in the same indication. Cross-resistance between tyrosine kinase inhibitors (TKIs) may be limited, even after failure with a previous VEGFR inhibitor, but the optimal sequence with TKIs remains to be determined. Randomized trials of second-line treatment options have showed either modest or no differences in terms of progression-free and overall survival (OS). Direct comparison between sorafenib and axitinib demonstrated differences in terms of PFS in favor of axitinib, but not in terms of OS as second-line treatment. In contrast, a phase III study showed a benefit in OS, favoring sorafenib when compared with temsirolimus. In conclusion, after using other VEGF inhibitor such as sunitinib, sorafenib is active and safe for the treatment of patients with advanced or metastatic RCC (AU)
Asunto(s)
Humanos , Masculino , Femenino , Proteínas Tirosina Quinasas/administración & dosificación , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/historia , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas/análisis , Proteínas Tirosina Quinasas/síntesis química , Relación Cintura-Cadera/métodosAsunto(s)
Alergia e Inmunología/historia , Diferenciación Celular/inmunología , Activación de Linfocitos/inmunología , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Animales , Diferenciación Celular/genética , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Activación de Linfocitos/genética , Proteínas Tirosina Quinasas/historia , Proteínas Tirosina Quinasas/fisiología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/historia , Receptores de Antígenos de Linfocitos T/fisiología , Transducción de Señal/genética , Sociedades Médicas/historia , Subgrupos de Linfocitos T/enzimologíaAsunto(s)
Agammaglobulinemia/historia , Enfermedades Genéticas Ligadas al Cromosoma X/historia , Proteínas Tirosina Quinasas/historia , Proto-Oncogenes , Familia-src Quinasas/clasificación , Agammaglobulinemia Tirosina Quinasa , Agammaglobulinemia/enzimología , Secuencia de Aminoácidos , Linfocitos B/enzimología , Linaje de la Célula , Mapeo Cromosómico , Cromosomas Humanos X/genética , Clonación Molecular , Secuencia de Consenso , Femenino , Tamización de Portadores Genéticos , Enfermedades Genéticas Ligadas al Cromosoma X/enzimología , Historia del Siglo XX , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/clasificación , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/genética , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Inactivación del Cromosoma XAsunto(s)
Agammaglobulinemia/historia , Enfermedades Genéticas Ligadas al Cromosoma X/historia , Proteínas Tirosina Quinasas/historia , Agammaglobulinemia Tirosina Quinasa , Agammaglobulinemia/enzimología , Linfocitos B/enzimología , Linaje de la Célula , Cromosomas Humanos X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/enzimología , Historia del Siglo XX , Humanos , Masculino , Células Mieloides/enzimología , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/aislamiento & purificaciónAsunto(s)
Proteínas de Ciclo Celular/historia , Proteínas de Ciclo Celular/metabolismo , Schizosaccharomyces/citología , Schizosaccharomyces/genética , Proteínas de Ciclo Celular/genética , Historia del Siglo XX , Mutación/genética , Proteínas Nucleares/genética , Proteínas Nucleares/historia , Proteínas Nucleares/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/historia , Proteínas Tirosina Quinasas/metabolismo , Proteínas de Schizosaccharomyces pombeRESUMEN
The Janus family of protein-tyrosine kinases has long been known to function in signal transduction pathways initiated by a host of cytokines. A brief overview of the role of Janus kinases (Jaks) in both cytokine and noncytokine signaling pathways highlights the broad physiologic importance of this kinase family. New insights into the structural and mechanistic regulatory aspects of Janus kinases are rapidly emerging. Recent mutational analyses allow the dissection of Jaks into three distinct structural domains governing receptor affiliation, autoregulation, and catalysis. A fourth domain determining substrate specificity is as yet poorly defined and is, therefore, discussed in the context of known substrates and inhibitors, a collection of molecules that have been expanded recently to include Stam and Jab. The proposed mechanism of the interconversion of Janus kinases from inactive to fully active enzymes involves three states of enzymatic activity. Additional layers of regulation can be independently superimposed on this multistate model, providing a simplified description of the behavior of Janus kinases under normal and pathologic circumstances.