Structure/function studies on the activation of the met receptorprotein-tyrosine kinase

Información del proyecto

Identificador del acuerdo de subvención: FMBI982972

Proyecto cerrado

Fecha de inicio 1 Diciembre 1998

Fecha de finalización 30 Noviembre 2000

Financiado con arreglo a

• Specific research and technological development programme in the field of the training and mobility of researchers, 1994-1998

Coste total

Sin datos

Aportación de la UE

Sin datos

Coordinado por

UNIVERSITY OF TORINO
Italy

Objetivo

Research objectives and content
Met is a receptor tyrosine kinase that elicits multiple biological responses including cell growth, scattering and tubulogenesis The autophosphorylation of two neighbouring tyrosine residues Y1234 and Y1235 in the kinase domain upregulates catalytic' activity and results in the phosphorylation of two tyrosines located in the cytoplasmic C-terminal tail Y1349 and Y1356 the mediates high affinity interactions with the SH2 domains of a number of signal transducers. Met is overexpressed in; significant number of carcinomas and is amplified in metastases. A direct genetic connection between Met activation an/ human cancer was demonstrated recently by the identification of causal mutations in the Met kinase domain for hereditary and sporadic papillary renal carcinomas (PRC). Some of these mutations have been shown to constitutively activate the receptor and when expressed in fibroblasts, form foci of transformation. Furthermore, all of the Met papillary renal carcinoma mutation are tumourigenic in nude mice. Therefore, single mutations have been identified in MET that convert the proto-oncogene to an oncogenic counterpart. The aims of the proposed study are: (1) to analyse the signalling pathways used by the Met receptor harbouring PRC mutations; (2) to define the structural basis for the oncogenic activation of the Met kinase by the resolution ofthe crystal structures of the wild-type and mutated Met tyrosine kinase domains.
Training content (objective, benefit and expected impact)
The objective of the candidate is to gain experience in the research of receptor tyrosine kineses and intracellular signalling pathways and their relation to human neoplastic disease. Dr. Tracy Williams will benefit from working in a research laboratory with a distinguished history in this area of research in which all necessary expertise is available to provide a thorough training in this field. Dr. Williams will be integrated into the the Cancer Research Institute (I.RC.C.) in Turin, Italy, under the direction of Professor Paolo Comoglio and will be supervised by Dr. Alberto Bardelli. The data accummulated from the research proposal is expected to be published in high impact international journals. Links with industry / industrial relevance (22)
We have an established collaboration with Pharmacia which aims to block Met activation and signalling, the research proposal of the candidate is directly relevant to this collaboration.

Ámbito científico (EuroSciVoc)

• ingeniería y tecnología › ingeniería de materiales › cristales
• ciencias naturales › ciencias biológicas › biología celular › comunicación celular
• humanidades › historia y arqueología › historia
• ciencias naturales › ciencias biológicas › genética › mutación
• ciencias médicas y de la salud › medicina clínica › oncología

Programa(s)

• FP4-TMR - Specific research and technological development programme in the field of the training and mobility of researchers, 1994-1998

Tema(s)

• 0302 - Post-doctoral research training grants
• TL02 - Molecular Biology and Biochemistry

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

RGI - Research grants (individual fellowships)

Coordinador

UNIVERSITY OF TORINO

• Aportación de la UE: Sin datos
• Dirección: 142,Strada Provinciale Km 3.95 142 University of Torino Medical School ; 10060 CANDIOLO ; Italia
• Coste total: Sin datos