Joseph Schlessinger (born Josip Schlessinger; 26 March 1945) is a Yugoslav-born Israeli-Americanbiochemist and biophysician. He is chair of the Pharmacology Department at Yale University School of Medicine in New Haven, Connecticut, as well as the founding director of the school's new Cancer Biology Institute.[1] His area of research is signaling through tyrosinephosphorylation, which is important in many areas of cellular regulation, especially growth control and cancer. Schlessinger's work has led to an understanding of the mechanism of transmembrane signaling by receptor tyrosine kinases[2] and how the resulting signals control cell growth and differentiation.
When Schlessinger was born on 26 March 1945 he was wrapped in a British military parachute. He was named for his grandfather. After World War II the family moved to Osijek, where another son, Darko David, was born. Imre Schlessinger once made a joke at the expense of Tito and was sentenced to several months in jail.[3][4]
The family moved to Israel in 1948.[5] Schlessinger served his compulsory military service with the Golani Brigade and was commissioned an officer. As part of his reserve duty he participated in the Six-Day War and the Yom Kippur War.[citation needed]
He is married to Irit Lax, also a professor in the pharmacology department at Yale. They each have two children by previous marriages.[5] In a 2009 interview with a Croatian daily newspaper Jutarnji list, he said, "Basically I am atheist. I grew up Jewish and I truly belong to the Jewish culture, but I'm not a follower of any world religion. Religion does not interest me at all."[3]
Academic career
Schlessinger was a member of the faculty of the Weizmann Institute from 1978 to 1991 and was the Ruth and Leonard Simon Professor of Cancer Research in the department of immunology from 1985 to 1991. In addition, he was a research director for Rorer Biotechnology in King of Prussia, Pennsylvania, from 1985 to 1990. In 1990, he was appointed as the Milton and Helen Kimmelman Professor and chairman of the department of pharmacology at the New York University School of Medicine. He served as director of NYU Medical Center's Skirball Institute for Biomolecular Medicine, from 1998 to 2001.[7]
Schlessinger is the recipient of numerous prizes, including the Michael Landau Prize (1973),[6] the Sara Leady Prize (1980),[6][13] the Hestrin Prize (1983),[6][13] the Levinson Prize (1984),[13] a Ciba-Drew Award (1995),[13] the Antoine Lacassagne Prize (1995),[13] the Taylor Prize (2000),[13][14] and the Dan David Prize (2006).[15][16]
In 2002, he was granted an honorary doctorate from the University of Haifa.[17] He has lectured at many institutions,[6] including the Harvey Society (in the 1993–1994 Harvey Lectures series)[18] and the 2006 Keith R. Porter Lecture of the American Society for Cell Biology.[19]
In 2012, the Hope Funds for Cancer Research selected Schlessinger to receive its Award of Excellence for Clinical Development. In 2009, Schlessinger was given an award by then-President of Croatia Stjepan Mesić for outstanding service in promoting Croatia in the international scientific community and for the contribution within Croatian biomedical sciences.[4]
According to PubMed, Schlessinger has authored over 450 scientific original and review articles in the areas of pharmacology, molecular biology, biochemistry, and structural biology, mostly on tyrosine kinase signaling. Tyrosine kinase signaling plays a critical role in the control of many cellular processes including cell proliferation, differentiation, metabolism, as well as cell survival and migration.[6]
Tyrosine kinases play a particularly important role in cancer, and several agents that block their activity are now used as anti-cancer drugs, such as Imatinib or Gleevec. Among his contributions are the findings that cell surface receptors with tyrosine kinase activity signal across membrane by forming dimers when they bind to their growth factor activators. He discovered this in studies of the epidermal growth factor receptor (EGFR). He was also instrumental in understanding how the SH2 domain controls tyrosine kinase signaling by binding to phosphorylated tyrosines in activated receptors. One of the seminal findings in this work was his laboratory's cloning of Grb2 and other Adaptor proteins.
Another is the lab's cloning of FRS2, which is critical for signaling by the Fibroblast growth factor receptor. In 2001, he was ranked by the ISI Highly Cited as one of the world's top 30 most cited scientists (across all fields) in the 1990s.[23] According to ISI, his papers have been cited a total of 76,699 times.[24]
In 2006, a sexual harassment lawsuit was initiated against Yale University by Schlessinger's former secretary, Mary Beth Garceau, who alleged numerous episodes of harassment during her employment at Yale[25][26][27][28] and claimed Yale University failed to act upon her frequent complaints, causing her to resign. The case was settled out of court in mid-2007 and the terms of the settlement were not publicly disclosed.[29]
SUGEN
In 1991, Schlessinger co-founded (with Axel Ullrich and Steven Evans-Freke) the biotechnology company SUGEN to develop ATP-like molecules that would compete with ATP for binding to the catalytic site of receptor tyrosine kinases in cancer treatment. In 1999, Sugen was acquired by Pharmacia & Upjohn for $650 million[30] and in 2003, Pharmacia was acquired by Pfizer.[31] One of the pipeline products (SU11248) was ultimately developed by Pfizer as Sutent (Sunitinib),[32] approved by the FDA for treating gastrointestinal stromal tumors and renal cell carcinoma.[33]
Plexxikon
In 2001, Schlessinger co-founded Plexxikon with Sung-Hou Kim (University of California, Berkeley). Plexxikon, uses a pioneering structural biology-based platform for drug discovery.[34] In April 2011, Plexxikon was acquired by the Japanese pharmaceutical company Daiichi Sankyo for $805 million and an additional $130 m in potential milestone payments.[35]
Kolltan Pharmaceuticals
In 2007, Schlessinger co-founded Kolltan Pharmaceuticals with Arthur Altschul Jr. Kolltan Pharmaceuticals is an early-stage biotech that develops antibodies to treat solid tumors.[36][37][38][39]
In April 2014, Kolltan received $60 million in equity financing.[40] In September 2014, Kolltan filed for an IPO and in January 2015, they withdrew the IPO.[41] In November 2016, Celldex Therapeutics acquired Kolltan for $235 million.[42]
Related Research Articles
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
In chemistry, dimerization is the process of joining two identical or similar molecular entities by bonds. The resulting bonds can be either strong or weak. Many symmetrical chemical species are described as dimers, even when the monomer is unknown or highly unstable.
The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.
Sunitinib, sold under the brand name Sutent, is an anti-cancer medication. It is a small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) in January 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications.
Axel Ullrich is a German cancer researcher and has been the director of the molecular biology department at the Max Planck Institute of Biochemistry in Martinsried, Germany since 1988. This department's research has primarily focused on signal transduction. Ullrich has received Hamdan Award for Medical Research Excellence, awarded by Sheikh Hamdan bin Rashid Al Maktoum Award for Medical Sciences, Dubai, United Arab Emirates in 2008 and Ullrich and his team received the Wolf Prize in 2010.
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.
Semaxanib is a tyrosine-kinase inhibitor drug designed by SUGEN as a cancer therapeutic. It is an experimental stage drug, not licensed for use on human patients outside clinical trials. Semaxanib is a potent and selective synthetic inhibitor of the Flk-1/KDR vascular endothelial growth factor (VEGF) receptor tyrosine kinase. It targets the VEGF pathway, and both in vivo and in vitro studies have demonstrated antiangiogenic potential.
The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.
Fibroblast growth factor receptor substrate 2 is a protein that in humans is encoded by the FRS2 gene.
Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.
SUGEN (Sugen) was a drug discovery company focused on development of protein kinase inhibitors. It was founded in 1991, and shut down in 2003, after developing the pioneering kinase inhibitor drug sunitinib (Sutent).
Plexxikon is an American drug discovery company based in South San Francisco, California. It was co-founded in 2001 by Joseph Schlessinger of Yale University, and Sung-Hou Kim of the University of California, Berkeley.
Nicholas B. Lydon FRS is a British scientist and entrepreneur. In 2009, he was awarded the Lasker Clinical Award and in 2012 the Japan Prize for the development of Gleevec, also known as Imatinib, a selective BCR-ABL inhibitor for the treatment of chronic myeloid leukaemia (CML), which converted a fatal cancer into a manageable chronic condition.
SU6656 is a Src family kinase inhibitor developed by the biotechnology company SUGEN Inc in 2000. SU6656 was initially identified as a Src kinase inhibitor by virtue of its ability to reverse an effect that an activated mutant form of Src has on the actin cytoskeleton, namely the formation of podosome rosettes, otherwise known as invadopodia. SU6656 was initially published as a Src family kinase inhibitor with selectivity relative to Platelet-derived growth factor receptor Tyrosine kinase. Subsequent studies have confirmed that SU6656 is relatively selective for Src family kinases, but some additional biochemical activities have been identified including: BRSK2, AMPK, Aurora C, Aurora B, CaMKKβ. The inhibition of these kinases in biochemical reactions in vitro does not necessarily indicate that these kinases are targets of SU6656 in cells.
Crenolanib besylate is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable benzimidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of class III receptor tyrosine kinases (RTK) FLT3, PDGFR α, and PDGFR β. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to phosphorylated active kinases with the ‘DFG in’ conformation motif.
György Kéri was a Hungarian biochemist, professor and Doctor of Biological Sciences (D.Sc.). His major field of research was signal transduction therapy and he participated in the development of novel drug discovery technologies and drug candidates that entered the clinical development process.
Anthony Rex Hunter is a British-American biologist who is a professor of biology at the Salk Institute for Biological Studies and the University of California San Diego. His research publications list his name as Tony Hunter.
Craig M. Crews is an American scientist at Yale University known for his contributions to chemical biology. He is known for his contributions to the field of induced proximity through his work in creating heterobifunctional molecules that "hijack" cellular processes by inducing the interaction of two proteins inside a living cell. His initial work focused on the discovery of PROteolysis-TArgeting Chimeras (PROTACs) to trigger degradation of disease-causing proteins, a process known as targeted protein degradation (TPD), and he has since developed new versions of -TACs to leverage other cellular processes and protein families to treat disease.
Mark Andrew Lemmon an English-born biochemist, is the Alfred Gilman Professor and Department Chair of Pharmacology at Yale University where he also directs the Cancer Biology Institute.
Karen L. Leach is an American biochemist with extensive drug discovery experience in large pharmaceutical research laboratories. Her expertise in molecular pharmacology, signal transduction and protein kinases, has been used to establish mechanisms of toxicity for therapeutics such as the novel antibiotic linezolid (Zyvox).
1 2 Ha-Kol (Glasilo Židovske zajednice u Hrvatskoj); Joseph Schlessinger odlikovan visokim Hrvatskim odličjem; stranica 54; broj 111, listopad/rujan 2009.(in Croatian)
1 2 "The long war". Info.med.yale.edu. 28 September 2010. Retrieved 16 January 2012.
↑ Nancy Imelda Schafer, ISI (18 October 2004). "ISI InCites Interview". In-cites.com. Archived from the original on 13 February 2009. Retrieved 16 January 2012.
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