Lewis C. Cantley
Encyclopedia
Lewis C. Cantley is an American cell biologist and biochemist and a professor in the Departments of Systems Biology and Medicine at Harvard Medical School
, and the Director of Cancer Research at the Beth Israel Deaconess Medical Center
, in Boston
, Massachusetts. Among his research contributions are the discovery and study of the enzyme PI-3-kinase, now known to be important to understanding cancer
and diabetes mellitus
.
, remaining in West Virginia at Wesleyan College
where he graduated summa cum laude in chemistry in 1971. Cantley obtained his Ph.D. at Cornell University
in Ithaca
, New York, where he worked with Gordon Hammes on enzyme kinetics, using FRET to study enzyme conformational changes. In 1975 he moved to Harvard University for a postdoctoral fellowship under Guido Guidotti, where he discovered that an impurity in commercial preparations of ATP, vanadate, acts as a transition state analog for phosphate hydrolysis. In 1978 Cantley became assistant professor of Biochemistry and Molecular Biology at Harvard, being promoted to associate professor in 1981. In 1985 he became a full professor in physiology at Tufts University School of Medicine
. In 1985 Cantley and colleagues Malcolm Whitman, David Kaplan, Tom Roberts, and Brian Schaffhausen made the seminal discovery of the existence of phosphoinositide-3-kinase (PI3K). In 1992, Cantley moved to Harvard Medical School as a Professor of Cell Biology and the Director of the Division of Signal Transduction at the former Beth Israel Hospital (now Beth Israel Deaconess Medical Center
). In 2003, Cantley became a founding member of the newly formed Department of Systems Biology at Harvard Medical School. In 2007 Cantley also became the Director of Cancer Research at the Beth Israel Deaconess Medical Center.
Cantley is married to Vicki Sato, herself a prominent figure in the pharmaceutical industry and a Professor at Harvard University.
kinase, that it is a novel type of phosphoinositide kinase that phosphorylates the 3' position on the inositol ring, and that this phosphatidylinositol-3-kinase (PI-3-kinase) is activated by growth factors to produce novel 3'-phosphorylated phosphoinositides, in particularly PtdIns(3,4,5)P3
. In subsequent years Cantley and colleagues identified critical aspects of the regulation of PI-3-kinase by growth factor receptors. Specifically, they discovered that the catalytic subunit p110 dimerizes with the regulatory subunit p85, and that the SH2 domain of p85 specifically recognized phosphotyrosines on growth factor receptors or adaptor proteins via the pY-X-X-M motif.
The Cantley lab has also made seminal contributions to understanding signaling downstream of PI-3-kinase. They discovered that the Pleckstrin Homology domain of AKT
binds to PtdIns(3,4,5)P3 (and PtdIns(3,4)P2) and that this binding is critical for activation of AKT catalytic activity. They further demonstrated that tuberin/TSC2
is a critical substrate of AKT, and together with the laboratory of John Blenis they discovered that AKT phosphorylation of tuberin/TSC2 is required for activation of mTOR TORC1 kinase activity via regulation of the small GTPase rheb
. The Cantley lab also was one of a few labs that nearly simultaneously identified LKB1 as a regulator of AMPK that also serves to regulate TORC1.
The fundamental and far-reaching nature of the discovery of PI-3-kinase, together with Cantley's role in mapping the upstream regulation of PI-3-kinase and the downstream signaling pathways, have led to speculation that Cantley is a likely candidate for the Nobel prize in Medicine or Physiology. The growing evidence for a primary role for PI-3-kinase in cancer and its critical role in insulin signaling have served to strengthen the significance of this fundamentally important discovery.
Subsequently the oriented peptide library approach was extended to identify the substrate specificity of protein kinases toward synthetic peptides. This approach was then extended to characterize the specificity of Ser/Thr kinases and phospho-Ser/Thr binding domains. This approach was used to characterize the substrate specificity of a large number of protein kinases. The kinase specificity matrices generated from these experiments served as the basis for creating the website Scansite, allowing the de novo identification of candidate phosphorylation sites in an arbitrary protein.
In later research, the oriented peptide library approach has also been used to characterize protease cleavage specificity. Modification of the original oriented peptide approach has allowed for large scale, kinome-wide determination of protein kinase specificity.
as a substrate to produce PtdIns(4,5)P2. Further research demonstrated that PtdIns(5)P is naturally occurring in all eukaryotes.
It is remarkable that of the seven naturally occurring phosphoinositides, the existence of four of them (PtdIns(5)P, PtdIns(3)P, PtdIns(3,4)P2, and PtdIns(3,4,5)P3) was discovered by Cantley and colleagues.
In recent years Cantley and colleagues have made additional links between metabolic regulation and oncogenic transformation with their discovery that the M2 isoform of pyruvate kinase is associated with cancer. This discovery provides a molecular basis for understanding the Warburg effect
. Cantley is now a major player in the resurgence of the importance of the Warburg effect in the process of oncogenesis.
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
, and the Director of Cancer Research at the Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center in Boston, Massachusetts is a major flagship teaching hospital of Harvard Medical School. It was formed out of the 1996 merger of Beth Israel Hospital and New England Deaconess Hospital...
, in Boston
Boston
Boston is the capital of and largest city in Massachusetts, and is one of the oldest cities in the United States. The largest city in New England, Boston is regarded as the unofficial "Capital of New England" for its economic and cultural impact on the entire New England region. The city proper had...
, Massachusetts. Among his research contributions are the discovery and study of the enzyme PI-3-kinase, now known to be important to understanding cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
and diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
.
Biography
Cantley grew up in West VirginiaWest Virginia
West Virginia is a state in the Appalachian and Southeastern regions of the United States, bordered by Virginia to the southeast, Kentucky to the southwest, Ohio to the northwest, Pennsylvania to the northeast and Maryland to the east...
, remaining in West Virginia at Wesleyan College
West Virginia Wesleyan College
West Virginia Wesleyan College is a regionally accredited private, coeducational, liberal arts college in Buckhannon, West Virginia, United States. It has an enrollment of about 1,400 students from 35 U.S. states and 26 countries. The school was founded in 1890 by the West Virginia Conference of...
where he graduated summa cum laude in chemistry in 1971. Cantley obtained his Ph.D. at Cornell University
Cornell University
Cornell University is an Ivy League university located in Ithaca, New York, United States. It is a private land-grant university, receiving annual funding from the State of New York for certain educational missions...
in Ithaca
Ithaca
Ithaca or Ithaka is an island located in the Ionian Sea, in Greece, with an area of and a little more than three thousand inhabitants. It is also a separate regional unit of the Ionian Islands region, and the only municipality of the regional unit. It lies off the northeast coast of Kefalonia and...
, New York, where he worked with Gordon Hammes on enzyme kinetics, using FRET to study enzyme conformational changes. In 1975 he moved to Harvard University for a postdoctoral fellowship under Guido Guidotti, where he discovered that an impurity in commercial preparations of ATP, vanadate, acts as a transition state analog for phosphate hydrolysis. In 1978 Cantley became assistant professor of Biochemistry and Molecular Biology at Harvard, being promoted to associate professor in 1981. In 1985 he became a full professor in physiology at Tufts University School of Medicine
Tufts University School of Medicine
The Tufts University School of Medicine is one of the eight schools that constitute Tufts University. Located on the university's health sciences campus in the Chinatown district of Boston, Massachusetts, the medical school has clinical affiliations with thousands of doctors and researchers in the...
. In 1985 Cantley and colleagues Malcolm Whitman, David Kaplan, Tom Roberts, and Brian Schaffhausen made the seminal discovery of the existence of phosphoinositide-3-kinase (PI3K). In 1992, Cantley moved to Harvard Medical School as a Professor of Cell Biology and the Director of the Division of Signal Transduction at the former Beth Israel Hospital (now Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center in Boston, Massachusetts is a major flagship teaching hospital of Harvard Medical School. It was formed out of the 1996 merger of Beth Israel Hospital and New England Deaconess Hospital...
). In 2003, Cantley became a founding member of the newly formed Department of Systems Biology at Harvard Medical School. In 2007 Cantley also became the Director of Cancer Research at the Beth Israel Deaconess Medical Center.
Cantley is married to Vicki Sato, herself a prominent figure in the pharmaceutical industry and a Professor at Harvard University.
Discovery of PI-3-kinase and PtdIns(3,4,5)P3
In a series of studies spanning several years, Cantley and colleagues demonstrated that a kinase activity associated with the middle T oncoprotein is a phosphoinositidePhosphatidylinositol
Phosphatidylinositol is a negatively charged phospholipid and a minor component in the cytosolic side of eukaryotic cell membranes....
kinase, that it is a novel type of phosphoinositide kinase that phosphorylates the 3' position on the inositol ring, and that this phosphatidylinositol-3-kinase (PI-3-kinase) is activated by growth factors to produce novel 3'-phosphorylated phosphoinositides, in particularly PtdIns(3,4,5)P3
Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
. In subsequent years Cantley and colleagues identified critical aspects of the regulation of PI-3-kinase by growth factor receptors. Specifically, they discovered that the catalytic subunit p110 dimerizes with the regulatory subunit p85, and that the SH2 domain of p85 specifically recognized phosphotyrosines on growth factor receptors or adaptor proteins via the pY-X-X-M motif.
The Cantley lab has also made seminal contributions to understanding signaling downstream of PI-3-kinase. They discovered that the Pleckstrin Homology domain of AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
binds to PtdIns(3,4,5)P3 (and PtdIns(3,4)P2) and that this binding is critical for activation of AKT catalytic activity. They further demonstrated that tuberin/TSC2
TSC2
Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
is a critical substrate of AKT, and together with the laboratory of John Blenis they discovered that AKT phosphorylation of tuberin/TSC2 is required for activation of mTOR TORC1 kinase activity via regulation of the small GTPase rheb
RHEB
GTP-binding protein Rheb also known as Ras homolog enriched in brain is a protein that in humans is encoded by the RHEB gene.- Function :Rheb is a recently discovered member of the Ras superfamily that may be involved in neural plasticity...
. The Cantley lab also was one of a few labs that nearly simultaneously identified LKB1 as a regulator of AMPK that also serves to regulate TORC1.
The fundamental and far-reaching nature of the discovery of PI-3-kinase, together with Cantley's role in mapping the upstream regulation of PI-3-kinase and the downstream signaling pathways, have led to speculation that Cantley is a likely candidate for the Nobel prize in Medicine or Physiology. The growing evidence for a primary role for PI-3-kinase in cancer and its critical role in insulin signaling have served to strengthen the significance of this fundamentally important discovery.
Use of Oriented Peptide Libraries to determine phosphopeptide binding specificity and protein kinase substrate specificity
In 1994, the Cantley lab published a novel strategy to determine the sequence specificity of phosphopeptide binding domains (initially SH2 domains).Subsequently the oriented peptide library approach was extended to identify the substrate specificity of protein kinases toward synthetic peptides. This approach was then extended to characterize the specificity of Ser/Thr kinases and phospho-Ser/Thr binding domains. This approach was used to characterize the substrate specificity of a large number of protein kinases. The kinase specificity matrices generated from these experiments served as the basis for creating the website Scansite, allowing the de novo identification of candidate phosphorylation sites in an arbitrary protein.
In later research, the oriented peptide library approach has also been used to characterize protease cleavage specificity. Modification of the original oriented peptide approach has allowed for large scale, kinome-wide determination of protein kinase specificity.
Discovery of PtdIns(5)P
In 1997, the Cantley lab discovered that the enzymes that had been referred to as type II PIP-kinases, instead of using PtdIns(4)P as a substrate, in fact required PtdIns(5)PPhosphatidylinositol 5-phosphate
Phosphatidylinositol 5-phosphate is one of the seven phosphoinositides, and is the last to have been discovered to be naturally occurring....
as a substrate to produce PtdIns(4,5)P2. Further research demonstrated that PtdIns(5)P is naturally occurring in all eukaryotes.
It is remarkable that of the seven naturally occurring phosphoinositides, the existence of four of them (PtdIns(5)P, PtdIns(3)P, PtdIns(3,4)P2, and PtdIns(3,4,5)P3) was discovered by Cantley and colleagues.
Role of metabolism in cancer
The role of PI-3-kinase in anabolic signaling by insulin, IGF-1, and other growth factors makes a straightforward link between metabolism and cancer, especially in light of the discovery that the PIK3CA gene encoding PI-3-kinase is an oncogene.In recent years Cantley and colleagues have made additional links between metabolic regulation and oncogenic transformation with their discovery that the M2 isoform of pyruvate kinase is associated with cancer. This discovery provides a molecular basis for understanding the Warburg effect
Warburg effect
The phrase "Warburg effect" is used for two unrelated observations in biochemistry, one in plant physiology and the other in oncology, both due to Nobel laureate Otto Heinrich Warburg.-Plant physiology:...
. Cantley is now a major player in the resurgence of the importance of the Warburg effect in the process of oncogenesis.
Industrial activities
Lewis C. Cantley has been involved in numerous companies. Recent examples include the following:- Co-founder of Agios Pharmaceuticals (with Tak Mak and Craig B. Thompson)
- Advisory Board of AVEO Pharmaceuticals
- Advisory Board of TransMolecular, Inc.
Awards and honors
Lewis C. Cantley has received numerous awards and honors, including:- Rolf Luft Award of the Karolinska Institute (2009)
- Pezcoller-AACR International Award for Cancer Research (2005)
- Caledonian Prize from the Royal Society of Edinburgh (2002)
- Elected to the National Academy of Sciences (2001)
- Heinrich Wieland PrizeHeinrich Wieland PrizeThe Heinrich Wieland Prize is an annual science award for research on lipids in the fields of chemistry, biochemistry, physiology and clinical medicine. It is sponsored by Boehringer Ingelheim, and awarded by a board of trustees...
for Lipid Research (2000) - Elected to the American Academy of Arts and Sciences (1999)
- ASBMB Avanti Award for Lipid Research (1998)