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Joseph Schlessinger, PhD

William H. Prusoff Professor of Pharmacology
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Additional Titles

Co-Director, Cancer Biology Institute

About

Titles

William H. Prusoff Professor of Pharmacology

Co-Director, Cancer Biology Institute

Appointments

Education & Training

PhD
Weizmann Institute of Science (1974)
MSc
Hebrew University of Jerusalem (1969)
BS
Hebrew University of Jerusalem (1968)

Research

Overview

Tyrosine phosphorylation plays a critical role in the control of many cellular processes including cell proliferation, differentiation, metabolism, as well as cell survival and migration. Receptor tyrosine kinases undergo ligand dependent dimerization which activates their intrinsic protein tyrosine kinase (PTK) domains. We have determined the crystal structure of Stem cell factor (SCF) and fibroblast growth factor (FGF), two ligands of receptor tyrosine kinases. In addition, we have determined the crystal structure of FGF in complex with the extracellular ligand binding domain of FGF-receptor (FGFR) and with a heparin sulfate oligosacchride. The structure of the ternary FGF/heparin/FGFR complex provides a molecular view of how FGF acts in concert with heparin to induce the dimerization and activation of FGF-receptors. We have also determined the crystal structure of the catalytic PTK domain of FGFR in complex with an ATP analogue or in complex with specific PTK inhibitors of FGFR activity and function. These structures enabled the development of new specific inhibitor for PTKs that are currently being tested in clinical trials. Receptor tyrosine kinases undergo ligand-dependent dimerization, which activates their intrinsic protein tyrosine kinase activity resulting in autophosphorylation and subsequent interaction and recruitment of multiple cellular target proteins. The phosphorylated tyrosine residues together with their immediate flanking sequences function as binding sites for signaling molecules containing src homology 2 (SH2) domains. Many signaling proteins carry SH2 domains plus one or more small protein modules such as SH3, PH, PTB, WW or FYVE domains. These protein modules function as mediator of protein-protein or protein-lipid interactions that are critical for signal transmission. In addition to direct recruitment by RTKs, many signaling proteins are recruited by an alternative mechanism involving a family of membrane linked docking proteins such as FRS-2a, and b, IRS-1 and 2, and Gab-1 and 2, among many others. Recruitment of signaling proteins by RTKs or by docking proteins leads to activation of multiple signaling pathways resulting in stimulation of a variety of cellular responses. The small adapter protein Grb2, for example, is bound through its SH3 domains to short, proline-rich sequences in the carboxy terminal tail of the guanine nucleotide-releasing factor Sos. Interaction between Grb2 and Sos with tyrosine phosphorylated RTKs or docking proteins results in translocation of Sos to the plasma membrane allowing the exchange of GDP for GTP on Ras. The activated GTP-bound form of Ras then starts a kinase cascade composed of Raf, MAPKK, and MAPK leading to phosphorylation of prooncogene Jun on serine and threonine residues to induce transcriptional activation. These and other signaling pathways that are activated by RTKs regulate multiple cellular processes. Many cancers and other diseases are caused by dysfunctions in RTKs or in components of their intracellular pathways.

Medical Subject Headings (MeSH)

Cell Proliferation; Crystallography, X-Ray; Drug Discovery; Pharmacology; Phosphorylation; Protein Kinases; Receptor Protein-Tyrosine Kinases; Signal Transduction

Research at a Glance

Yale Co-Authors

Frequent collaborators of Joseph Schlessinger's published research.

Publications

2024

2015

2014

Academic Achievements & Community Involvement

  • honor

    Clifford Prize for Cancer Research

  • honor

    BBVA Foundation Frontiers of Knowledge Award

  • honor

    AACR International Award for Cancer

  • honor

    Medal of Danica Hrvatska Order, Republic of Croatia

  • honor

    Elected as a foreign member of the Croatian Academy of Science

Get In Touch

Contacts

Academic Office Number
Lab Number
Mailing Address

Pharmacology

PO Box 208066, 333 Cedar Street

New Haven, CT 06520-8066

United States

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