Much research effort in the context of control of cellular signaling responses focuses on protein kinases and the role of protein phosphorylation. The study of CML is no exception. The identification of the Philadelphia chromosome focussed attention on the role of the p210 bcr/abl protein tyrosine kinase. however phosphorylation is a reversible process in vivo and this project will focus on the contribution of the protein tyrosine phosphatases (PTPs). This project offers protein chemical and molecular/cell biological approaches to the study of PTPs with respect to their involvement in CML. The broad, long term objective of these studies is to identify and characterize PTPs as potential antagonists of the aberrant tyrosine phosphorylation associated with the Ph+ CML phenotype. The health relatedness of the project is that through the identification and characterization of PTPs that antagonize the function of p210 bcr/abl, new insights will be provided into the molecular mechanisms underlying CML and new potential targets for therapeutic intervention will be discovered.
The specific aims are as follows: 1. To define the effects of PTP1B on signaling events initiated by p210 bcr/abl. 2. To define the effects of p210 bcr/abl on PTP1B in terms of: a) characterization of the changes in phosphorylation of PTP1B that are observed following expression of p210 bcr/abl; and b) identification nd characterization of potential regulatory proteins that interact with PTP1B in a p210 bcr/abl dependent manner. 3. To test the effects of other PTPs on p210 bcr/abl induced signaling events. 4. To characterize novel PTPs in CML model systems and in human patient samples.
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