Lewis C. Cantley

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Lewis C. Cantley
Born (1949-02-20) February 20, 1949
West Virginia, United States
Residence Boston, Massachusetts
Citizenship United States
Nationality American
Fields Biochemistry
Cell Biology
Systems Biology
Institutions Weill Cornell Medical College
Harvard Medical School
Beth Israel Deaconess Medical Center
Tufts University
Harvard University
Alma mater Wesleyan College
Cornell University
Doctoral advisor Gordon Hammes
Other academic advisors Guido Guidotti
Known for PI-3-kinase
Phosphatidylinositol (3,4,5)-trisphosphate
Oriented Peptide Libraries/Scansite
Phosphatidylinositol 5-phosphate

Lewis C. Cantley (born February 20, 1949) 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.[1][2] He has recently moved to Weill Cornell Medical College in New York City.

Biography [1][2][3]

Cantley grew up in West Virginia, 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.

Research

Discovery of PI-3-kinase and PtdIns(3,4,5)P3[1][2][4]

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,[5] that it is a novel type of phosphoinositide kinase that phosphorylates the 3' position on the inositol ring,[6] 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.[7] 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,[8] and that the SH2 domain of p85 specifically recognized phosphotyrosines[9] on growth factor receptors or adaptor proteins via the pY-X-X-M motif.[10][11]

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.[12][13] They further demonstrated that tuberin/TSC2 is a critical substrate of AKT,[14] 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[15] via regulation of the small GTPase rheb.[16] 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.[17][18]

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."[19] 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.[20] The growing evidence for a primary role for PI-3-kinase in cancer[21][22] and its critical role in insulin signaling[23] 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).[10] Subsequently the oriented peptide library approach was extended to identify the substrate specificity of protein kinases toward synthetic peptides.[24] This approach was then extended to characterize the specificity of Ser/Thr kinases and phospho-Ser/Thr binding domains.[25] 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.[26][27]

In later research, the oriented peptide library approach has also been used to characterize protease cleavage specificity.[28] Modification of the original oriented peptide approach has allowed for large scale, kinome-wide determination of protein kinase specificity.[29]

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.[30] 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.[6][7][30][31]

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.[32]

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.[33][34] 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.[35]

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)[36]
  • Advisory Board of AVEO Pharmaceuticals [37]
  • Advisory Board of TransMolecular, Inc.[38]

Awards, honors and media appearances

Cantley has received numerous awards and honors, including:

  • Rolf Luft Award of the Karolinska Institute (2009)[39]
  • Pezcoller-AACR International Award for Cancer Research (2005)[40]
  • Caledonian Prize from the Royal Society of Edinburgh (2002)[41]
  • Elected to the National Academy of Sciences (2001) [1]
  • Heinrich Wieland Prize for Lipid Research (2000)
  • Elected to the American Academy of Arts and Sciences (1999)[42]
  • ASBMB Avanti Award for Lipid Research (1998)
  • Breakthrough Prize in Life Sciences (2013)

He appeared in the 60 minutes program "Is sugar toxic?".[43]

References

  1. ↑ 1.0 1.1 1.2 1.3 Bradley D (March 2004). "Biography of Lewis C. Cantley". Proc. Natl. Acad. Sci. U.S.A. 101 (10): 3327–8. Bibcode:2004PNAS..101.3327B. doi:10.1073/pnas.0400872101. PMC 373460. PMID 14993589. 
  2. ↑ 2.0 2.1 2.2 Cantley LC (July 2009). "Lewis C. Cantley". Curr. Biol. 19 (14): R540–1. doi:10.1016/j.cub.2009.06.010. PMID 19655422. 
  3. ↑ Alberta Cancer Foundation International Advisory Board
  4. ↑ Cantley, LC. "From Kinase to Cancer." The Scientist, December 2007.
  5. ↑ Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM (1985). "Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation". Nature 315 (6016): 239–42. Bibcode:1985Natur.315..239W. doi:10.1038/315239a0. PMID 2987699. 
  6. ↑ 6.0 6.1 Whitman M, Downes CP, Keeler M, Keller T, Cantley L (April 1988). "Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate". Nature 332 (6165): 644–6. Bibcode:1988Natur.332..644W. doi:10.1038/332644a0. PMID 2833705. 
  7. ↑ 7.0 7.1 Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC (April 1989). "PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells". Cell 57 (1): 167–75. doi:10.1016/0092-8674(89)90182-7. PMID 2467744. 
  8. ↑ Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, Cantley LC (November 1990). "Purification and characterization of phosphoinositide 3-kinase from rat liver". J. Biol. Chem. 265 (32): 19704–11. PMID 2174051. 
  9. ↑ Carpenter CL, Auger KR, Chanudhuri M, et al. (May 1993). "Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit". J. Biol. Chem. 268 (13): 9478–83. PMID 7683653. 
  10. ↑ 10.0 10.1 Songyang Z, Shoelson SE, Chaudhuri M, et al. (March 1993). "SH2 domains recognize specific phosphopeptide sequences". Cell 72 (5): 767–78. doi:10.1016/0092-8674(93)90404-E. PMID 7680959. 
  11. ↑ Yoakim M, Hou W, Songyang Z, Liu Y, Cantley L, Schaffhausen B (September 1994). "Genetic analysis of a phosphatidylinositol 3-kinase SH2 domain reveals determinants of specificity". Mol. Cell. Biol. 14 (9): 5929–38. PMC 359119. PMID 8065326. 
  12. ↑ Franke TF, Kaplan DR, Cantley LC, Toker A (January 1997). "Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate". Science 275 (5300): 665–8. doi:10.1126/science.275.5300.665. PMID 9005852. 
  13. ↑ Rameh LE, Arvidsson A, Carraway KL, et al. (August 1997). "A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains". J. Biol. Chem. 272 (35): 22059–66. doi:10.1074/jbc.272.35.22059. PMID 9268346. 
  14. ↑ Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (July 2002). "Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway". Mol. Cell 10 (1): 151–62. doi:10.1016/S1097-2765(02)00568-3. PMID 12150915. 
  15. ↑ Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J (October 2002). "Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13571–6. Bibcode:2002PNAS...9913571T. doi:10.1073/pnas.202476899. PMC 129715. PMID 12271141. 
  16. ↑ Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J (August 2003). "Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb". Curr. Biol. 13 (15): 1259–68. doi:10.1016/S0960-9822(03)00506-2. PMID 12906785. 
  17. ↑ Shaw RJ, Kosmatka M, Bardeesy N, et al. (March 2004). "The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress". Proc. Natl. Acad. Sci. U.S.A. 101 (10): 3329–35. Bibcode:2004PNAS..101.3329S. doi:10.1073/pnas.0308061100. PMC 373461. PMID 14985505. 
  18. ↑ Shaw RJ, Bardeesy N, Manning BD, et al. (July 2004). "The LKB1 tumor suppressor negatively regulates mTOR signaling". Cancer Cell 6 (1): 91–9. doi:10.1016/j.ccr.2004.06.007. PMID 15261145. 
  19. ↑ "Dr. Lewis Cantley Awarded $3 Million Breakthrough Prize in Life Sciences for Excellence in Cancer Research". Press Release, Weill Cornell Medical College. Feb 21, 2013. Retrieved 1 November 2013. 
  20. ↑ Palazzo, Alex (October 1, 2008). "Gaze into the crystal ball – Nobel Prize Predictions". Transcription and Translation. ScienceBlogs. Retrieved 1 November 2013. 
  21. ↑ Courtney KD, Corcoran RB, Engelman JA (February 2010). "The PI3K pathway as drug target in human cancer". J. Clin. Oncol. 28 (6): 1075–83. doi:10.1200/JCO.2009.25.3641. PMC 2834432. PMID 20085938. 
  22. ↑ Wong KK, Engelman JA, Cantley LC (February 2010). "Targeting the PI3K signaling pathway in cancer". Curr. Opin. Genet. Dev. 20 (1): 87–90. doi:10.1016/j.gde.2009.11.002. PMC 2822054. PMID 20006486. 
  23. ↑ Cantley LC (May 2002). "The phosphoinositide 3-kinase pathway". Science 296 (5573): 1655–7. Bibcode:2002Sci...296.1655C. doi:10.1126/science.296.5573.1655. PMID 12040186. 
  24. ↑ Songyang Z, Blechner S, Hoagland N, Hoekstra MF, Piwnica-Worms H, Cantley LC (November 1994). "Use of an oriented peptide library to determine the optimal substrates of protein kinases". Curr. Biol. 4 (11): 973–82. doi:10.1016/S0960-9822(00)00221-9. PMID 7874496. 
  25. ↑ Yaffe MB, Rittinger K, Volinia S, et al. (December 1997). "The structural basis for 14-3-3:phosphopeptide binding specificity". Cell 91 (7): 961–71. doi:10.1016/S0092-8674(00)80487-0. PMID 9428519. 
  26. ↑ Yaffe MB, Leparc GG, Lai J, Obata T, Volinia S, Cantley LC (April 2001). "A motif-based profile scanning approach for genome-wide prediction of signaling pathways". Nat. Biotechnol. 19 (4): 348–53. doi:10.1038/86737. PMID 11283593. 
  27. ↑ Obenauer JC, Cantley LC, Yaffe MB (July 2003). "Scansite 2.0: Proteome-wide prediction of cell signaling interactions using short sequence motifs". Nucleic Acids Res. 31 (13): 3635–41. doi:10.1093/nar/gkg584. PMC 168990. PMID 12824383. 
  28. ↑ Turk BE, Huang LL, Piro ET, Cantley LC (July 2001). "Determination of protease cleavage site motifs using mixture-based oriented peptide libraries". Nat. Biotechnol. 19 (7): 661–7. doi:10.1038/90273. PMID 11433279. 
  29. ↑ Hutti JE, Jarrell ET, Chang JD, et al. (October 2004). "A rapid method for determining protein kinase phosphorylation specificity". Nat. Methods 1 (1): 27–9. doi:10.1038/nmeth708. PMID 15782149. 
  30. ↑ 30.0 30.1 Rameh LE, Tolias KF, Duckworth BC, Cantley LC (November 1997). "A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate". Nature 390 (6656): 192–6. Bibcode:1997Natur.390..192R. doi:10.1038/36621. PMID 9367159. 
  31. ↑ Auger KR, Carpenter CL, Cantley LC, Varticovski L (December 1989). "Phosphatidylinositol 3-kinase and its novel product, phosphatidylinositol 3-phosphate, are present in Saccharomyces cerevisiae". J. Biol. Chem. 264 (34): 20181–4. PMID 2555343. 
  32. ↑ Samuels Y, Wang Z, Bardelli A, et al. (April 2004). "High frequency of mutations of the PIK3CA gene in human cancers". Science 304 (5670): 554. doi:10.1126/science.1096502. PMID 15016963. 
  33. ↑ Christofk HR, Vander Heiden MG, Harris MH, et al. (March 2008). "The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth". Nature 452 (7184): 230–3. Bibcode:2008Natur.452..230C. doi:10.1038/nature06734. PMID 18337823. 
  34. ↑ Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC (March 2008). "Pyruvate kinase M2 is a phosphotyrosine-binding protein". Nature 452 (7184): 181–6. Bibcode:2008Natur.452..181C. doi:10.1038/nature06667. PMID 18337815. 
  35. ↑ Vander Heiden MG, Cantley LC, Thompson CB (May 2009). "Understanding the Warburg effect: the metabolic requirements of cell proliferation". Science 324 (5930): 1029–33. Bibcode:2009Sci...324.1029V. doi:10.1126/science.1160809. PMC 2849637. PMID 19460998. 
  36. ↑ Agios Pharmaceuticals
  37. ↑ AVEO Pharmaceuticals
  38. ↑ TransMolecular, Inc.
  39. ↑ Karolinska Institute
  40. ↑ EurekAlert! 7-Apr-2005
  41. ↑ Royal Society of Edinburgh Prizes
  42. ↑ AAAS Membership
  43. ↑ "Is Sugar Toxic? 60 Minutes report". 

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