Lewis C. Cantley

Last updated
Lewis C. Cantley
Born (1949-02-20) February 20, 1949 (age 75)
West Virginia, U.S.
Alma mater West Virginia Wesleyan College
Cornell University
Known for PI-3-kinase
Phosphatidylinositol (3,4,5)-trisphosphate
Oriented Peptide Libraries/Scansite
Phosphatidylinositol 5-phosphate
Scientific career
Fields Biochemistry
Cell Biology
Systems Biology
Institutions Weill Cornell Medical College
Harvard Medical School
Beth Israel Deaconess Medical Center
Tufts University
Harvard University
Doctoral advisor Gordon Hammes
Other academic advisorsGuido Guidotti

Lewis C. Cantley (born February 20, 1949) is an American cell biologist and biochemist who has made significant advances to the understanding of cancer metabolism. Among his most notable contributions are the discovery and study of the enzyme PI-3-kinase, now known to be important to understanding cancer and diabetes mellitus. [1] [2] He is currently Meyer Director and Professor of Cancer Biology at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City. He was formerly 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. In 2016, he was elected Chairman of the Board for the Hope Funds for Cancer Research.

Contents

Biography

Cantley grew up in West Virginia, remaining there at Wesleyan College where he graduated summa cum laude in chemistry in 1971. Cantley obtained his PhD 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. He joined the faculty of Weill Cornell Medicine and NewYork–Presbyterian Hospital in 2012. [1] [2] [3] [4] Dr. Cantley was elected the Chairman of the Board of the Hope Funds for Cancer Research in 2016. [5]

Cantley is married to Vicki Sato, herself a prominent figure in the pharmaceutical industry and a professor at Harvard University in both the Business and Medical Schools.

Research

Discovery of PI-3-kinase and PtdIns(3,4)P2 [1] [2] [6]

In a series of studies spanning several years, Cantley and colleagues demonstrated that a kinase activity associated with the middle T oncoprotein is a phosphoinositide kinase, [7] that it is a novel type of phosphoinositide kinase that phosphorylates the 3' position on the inositol ring, [8] 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 [9] that had previously been identified in physiologically stimulated human neutrophils. [10] 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, [11] and that the SH2 domain of p85 specifically recognized phosphotyrosines [12] on growth factor receptors or adaptor proteins via the pY-X-X-M motif. [13] [14]

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. [15] [16] They further demonstrated that tuberin/TSC2 is a critical substrate of AKT, [17] 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 [18] via regulation of the small GTPase rheb. [19] 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. [20] [21]

For the discovery of PI-3-Kinase and its role in cancer metabolism, Cantley was one of eleven recipients of the inaugural Breakthrough Prize in Life Sciences, "the world's richest academic prize for medicine and biology. The prize, which carries a $3 million cash award, recognizes excellence in research aimed at curing intractable diseases and human life." [22] 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. [23] The growing evidence for a primary role for PI-3-kinase in cancer [24] [25] and its critical role in insulin signaling [26] have served to strengthen the significance of this fundamentally important discovery.

The first drug targeting the PI-3-kinase pathway as a treatment for cancer - Idelalisib (PI3K Delta inhibitor) - was approved by the FDA as a treatment for leukemia and two types of lymphoma in July 2014. [27] Other drugs are currently in clinical development.

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). [13] Subsequently, the oriented peptide library approach was extended to identify the substrate specificity of protein kinases toward synthetic peptides. [28] This approach was then extended to characterize the specificity of Ser/Thr kinases and phospho-Ser/Thr binding domains. [29] 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. [30] [31]

In later research, the oriented peptide library approach has also been used to characterize protease cleavage specificity. [32] Modification of the original oriented peptide approach has allowed for large scale, kinome-wide determination of protein kinase specificity. [33]

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)P as a substrate to produce PtdIns(4,5)P2. [34] 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. [8] [9] [34] [35]

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. [36]

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. [37] [38] 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. [39]

Role of PI-3-kinase in different cancers

Cantley was part of the Stand Up to Cancer "dream team" that was brought together to investigate ways to target PI-3-kinase as a way to treat women's cancers, and he now leads a national effort targeting triple-negative breast cancer and ovarian cancer with novel drug combinations. [40] Recent research found that high levels of Vitamin C halted the growth of aggressive forms of colorectal tumors. [41] His lab also elucidated the role of Nrf2 in serine production in non-small cell lung cancer, with potential implications for pancreatic and other cancers as well. [42]

Industrial activities

Lewis C. Cantley has been involved in numerous companies. Recent examples include the following:

Awards, honors and media appearances

Cantley has received numerous awards and honors, including:

He appeared in the 60 Minutes program "Is sugar toxic?". [63]

Related Research Articles

<span class="mw-page-title-main">Phosphatidylinositol</span> Signaling molecule

Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found in eukaryotes, and was found to be a signaling molecule.

<span class="mw-page-title-main">Phosphatidylinositol (3,4,5)-trisphosphate</span> Chemical compound

Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid that resides on the plasma membrane.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

<span class="mw-page-title-main">P110α</span> Human protein-coding gene

The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, also called p110α protein, is a class I PI 3-kinase catalytic subunit. The human p110α protein is encoded by the PIK3CA gene.

<span class="mw-page-title-main">Phosphatidylinositol 4,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.

<span class="mw-page-title-main">Phosphatidylinositol 3-phosphate</span> Chemical compound

Phosphatidylinositol 3-phosphate (PI3P) is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and III phosphoinositide 3-kinases activity on phosphatidylinositol.

<span class="mw-page-title-main">Phosphatidylinositol 3,4-bisphosphate</span>

Phosphatidylinositol (3,4)-bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)P2 at the plasma membrane activates a number of important cell signaling pathways.

<span class="mw-page-title-main">P110δ</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform or p110δ is an enzyme that in humans is encoded by the PIK3CD gene.

<span class="mw-page-title-main">Phosphatidylinositol 3,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 3,5-bisphosphate is one of the seven phosphoinositides found in eukaryotic cell membranes. In quiescent cells, the PtdIns(3,5)P2 levels, typically quantified by HPLC, are the lowest amongst the constitutively present phosphoinositides. They are approximately 3 to 5-fold lower as compared to PtdIns3P and PtdIns5P levels, and more than 100-fold lower than the abundant PtdIns4P and PtdIns(4,5)P2. PtdIns(3,5)P2 was first reported to occur in mouse fibroblasts and budding yeast S. cerevisiae in 1997. In S. cerevisiae PtdIns(3,5)P2 levels increase dramatically during hyperosmotic shock. The response to hyperosmotic challenge is not conserved in most tested mammalian cells except for differentiated 3T3L1 adipocytes.

<span class="mw-page-title-main">PX domain</span>

The PX domain is a phosphoinositide-binding structural domain involved in targeting of proteins to cell membranes.

<span class="mw-page-title-main">PIK3R1</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the PIK3R1 gene.

<span class="mw-page-title-main">PIK3CB</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta isoform is an enzyme that in humans is encoded by the PIK3CB gene.

<span class="mw-page-title-main">PIK3C2A</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing alpha polypeptide is an enzyme that in humans is encoded by the PIK3C2A gene.

<span class="mw-page-title-main">PIK3C3</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol 3-kinase catalytic subunit type 3 is an enzyme subunit that in humans is encoded by the PIK3C3 gene. It's a class III phosphoinositide 3-kinase.

<span class="mw-page-title-main">PI4KB</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol 4-kinase beta is an enzyme that in humans is encoded by the PI4KB gene.

<span class="mw-page-title-main">PIKFYVE</span> Protein-coding gene in the species Homo sapiens

PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene.

<span class="mw-page-title-main">PIP4K2A</span> Kinase enzyme

Phosphatidylinositol-5-phosphate 4-kinase type-2 alpha is an enzyme that in humans is encoded by the PIP4K2A gene.

<span class="mw-page-title-main">PIP4K2B</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol-5-phosphate 4-kinase type-2 beta is an enzyme that in humans is encoded by the PIP4K2B gene.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

Phosphatidylinositol 5-phosphate (PtdIns5P) is a phosphoinositide, one of the phosphorylated derivatives of phosphatidylinositol (PtdIns), that are well-established membrane-anchored regulatory molecules. Phosphoinositides participate in signaling events that control cytoskeletal dynamics, intracellular membrane trafficking, cell proliferation and many other cellular functions. Generally, phosphoinositides transduce signals by recruiting specific phosphoinositide-binding proteins to intracellular membranes.

References

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  45. ↑ Volastra Therapeutics
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  48. ↑ AVANTI AWARD IN LIPIDS
  49. ↑ AAAS Membership
  50. ↑ Royal Society of Edinburgh Prizes
  51. ↑ EurekAlert! 7-Apr-2005
  52. ↑ Karolinska Institute Archived 2011-07-18 at the Wayback Machine
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  62. ↑ Louisa Gross Horwitz Prize 2019
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