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Cell Signaling By Receptor Tyrosine Kinases: From Basic Principles To Cancer Therapy

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Air date: Wednesday, September 10, 2008, 3:00:00 PM
Time displayed is Eastern Time, Washington DC Local
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Category: WALS - Wednesday Afternoon Lectures
Runtime: 01:00:54
Description: Receptor tyrosine kinases (RTKs) comprise a large family of cell surface receptors that control many critical cellular processes. Various human diseases are caused by dysfunction in RTKs or in their intracellular signaling pathways. Stem Cell Factor (SCF) initiates its multiple cellular responses by binding to the extracellular region of the RTK KIT, resulting in receptor dimerization and tyrosine kinase activation.

We have determined the crystal structure of the entire extracellular region of KIT before and after SCF stimulation. The structures show that Kit dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together. Receptor dimerization is followed by conformational changes that enable lateral interactions between membrane proximal Ig-like domains D4 and D5 of two KIT molecules. Experiments with cultured cells show that KIT activation is compromised by point mutations in amino acids critical for D4-D4 interaction. Moreover, a variety of oncogenic mutations are mapped to the D5-D5 interface. Since key hallmarks of KIT structures, ligand-induced receptor dimerization and the critical residues in the D4-D4 interface are conserved in other receptors, the mechanism of KIT stimulation underlies the mechanism of activation of many RTKs.

Sutent/SU11248 is a new drug that blocks the actions of KIT, PDGF receptor, VEGF receptor and RET. Sutent has been approved by the FDA for the treatment of gastrointestinal stromal tumors (GIST) and for advanced kidney cancers. The approval marks the first time the FDA has approved a new oncology product for two indications simultaneously.

Joseph Schlessinger has been the William H. Prusoff Professor and Chairman of the Department of Pharmacology at Yale University School of Medicine since 2001. He was the Director of the Skirball Institute for Biomolecular Medicine at New York University (NYU) Medical Center from 1998-2001 and the Milton and Helen Kimmelman Professor and Chairman of the Department of Pharmacology at NYU Medical School from 1990-2001. He was a member of the faculty of the Weizmann Institute from 1978-1991 and the Ruth and Leonard Simon Professor of Cancer Research in the Department of Immunology from 1985-1991. Joseph Schlessinger was a Research Director for Rorer Biotechnology from 1985-1990. He co-founded Sugen, Inc. in 1991 and Plexxikon in 2001. He is currently the Chairman of the Board of Plexxikon and a member of the Scientific Advisory Board of the company.

Schlessinger received a B.Sc. degree in Chemistry and Physics in 1968 (magna cum laude), and a M.Sc. degree in chemistry (magna cum laude) in 1970 from the Hebrew University in Jerusalem. He obtained a Ph.D. degree in biophysics from the Weizmann Institute of Science in 1974. From 1974-1976, he was a postdoctoral fellow in the Departments of Chemistry and Applied Physics at Cornell University, and from 1977-1978, he was a visiting fellow in the immunology branch of the National Cancer Institute of NIH.

For more information, visit http://info.med.yale.edu/pharm/chairman
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NLM Title: Cell signaling by receptor tyrosine kinases : from basic principles to cancer therapy [electronic resource] / Joseph Schlessinger.
Series: NIH director's Wednesday afternoon lecture series
Author: Schlessinger, Joseph.
National Institutes of Health (U.S.)
Publisher:
Other Title(s): NIH director's Wednesday afternoon lecture series
Abstract: (CIT): Receptor tyrosine kinases (RTKs) comprise a large family of cell surface receptors that control many critical cellular processes. Various human diseases are caused by dysfunction in RTKs or in their intracellular signaling pathways. Stem Cell Factor (SCF) initiates its multiple cellular responses by binding to the extracellular region of the RTK KIT, resulting in receptor dimerization and tyrosine kinase activation. We have determined the crystal structure of the entire extracellular region of KIT before and after SCF stimulation. The structures show that Kit dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together. Receptor dimerization is followed by conformational changes that enable lateral interactions between membrane proximal Ig-like domains D4 and D5 of two KIT molecules. Experiments with cultured cells show that KIT activation is compromised by point mutations in amino acids critical for D4-D4 interaction. Moreover, a variety of oncogenic mutations are mapped to the D5-D5 interface. Since key hallmarks of KIT structures, ligand-induced receptor dimerization and the critical residues in the D4-D4 interface are conserved in other receptors, the mechanism of KIT stimulation underlies the mechanism of activation of many RTKs. Sutent/SU11248 is a new drug that blocks the actions of KIT, PDGF receptor, VEGF receptor and RET. Sutent has been approved by the FDA for the treatment of gastrointestinal stromal tumors (GIST) and for advanced kidney cancers. The approval marks the first time the FDA has approved a new oncology product for two indications simultaneously.
Subjects: Antineoplastic Agents
Dimerization
Receptor Protein-Tyrosine Kinases
Signal Transduction
Stem Cell Factor
Publication Types: Lectures
Webcasts
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NLM Classification: QU 141
NLM ID: 101486624
CIT Live ID: 7014
Permanent link: http://videocast.nih.gov/launch.asp?14634

 

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