BADERC-Lewis Cantley

Lewis Cantley, Ph.D.

Signal Transduction Pathways that Control Metabolism

The major research objective of this laboratory is to understand the biochemical pathways that regulate normal mammalian cell growth and the defects that cause cell transformation. More than 20 years ago this laboratory discovered phosphoinositide 3-Kinase (PI3K) as an enzyme that co-purified with a variety of oncoproteins (Whitman et al., 1988). Subsequent research from this laboratory and other laboratories showed that PI3K activation is critical for oncogene-mediated cell transformation, as well as for insulin-dependent stimulation of glucose uptake and metabolism. Further work from this laboratory and other laboratories revealed that lipid products of PI3K directly activate the AKT/PKB protein kinase to provide a cell survival signal (Franke et al., 1997). This discovery, as well as subsequent discoveries from other laboratories that human cancers frequently have activating mutations in PI3K genes and/or inactivating mutations in the PTEN gene (encoding a phosphatase that degrades PI3K lipid products) stimulated pharmaceutical companies to develop PI3K pathway inhibitors for cancer therapy. The Cantley laboratory is currently utilizing mouse models, genetically engineered with mutations in the PI3K pathway, to investigate opportunities for therapeutic intervention in diseases that result from defects in the PI3K pathway (Fruman et al., 1999, 2000; Ueki et al., 2002A, 2002B, 2003; Brachmann et al., 2005A, 2005B; Luo et al., 2005, Yuan et al., 2008; Engelman et al., 2008).

Recent studies from this laboratory have revealed that growth factors, through activation of PI3K and other signaling pathways, cause major changes in cellular metabolism that are critical for the growth of cancer cells. Of particular interest, cancer cells invariably utilize an embryonic form of pyruvate kinase (PKM2) to channel glucose metabolites for optimal cell growth (Christofk et al., 2008A, 2008B). Ongoing studies are defining how oncogene transformation of cells alters the flux of metabolites such as glucose and glutamine and how these changes enhance cell growth and cell survival.

Another major focus of this laboratory is the structural basis for specificity in protein/protein interactions in signal transduction cascades that control cell growth and survival. In particular, this laboratory has focused on the mechanism by which protein phosphorylation can control the assembly of signaling complexes. A novel oriented peptide library technique was developed to determine optimal phosphopeptides for binding to various protein domains (Songyang et al., 1993). This technique was subsequently modified to determine optimal substrates for protein kinases (Songyang et al., 1994, 1995, 1996; Hutti et al., 2004). The identification of optimal peptides has facilitated the determination of the structure of protein-peptide complexes and explained how specificity in signaling is maintained (Yaffe et al., 1997A, 1997B; Elia et al., 2003A, 2003B; Benes et al., 2005). These studies have also led to a bioinformatics approach (Scansite) for predicting sites of protein phosphorylation and protein interaction from primary sequences (Yaffe et al., 2001; Obenauer et al., 2003).

References:

Zheng B, Cantley LC. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):819-22. Epub 2007 Jan 4.

Holt LJ, Hutti JE, Cantley LC, Morgan DO. Evolution of Ime2 phosphorylation sites on Cdk1 substrates provides a mechanism to limit the effects of the phosphatase Cdc14 in meiosis. Mol Cell. 2007 Mar 9;25(5):689-702.

Hurov JB, Huang M, White LS, Lennerz J, Choi CS, Cho YR, Kim HJ, Prior JL, Piwnica-Worms D, Cantley LC, Kim JK, Shulman GI, Piwnica-Worms H. Loss of the Par-1b/MARK2 polarity kinase leads to increased metabolic rate, decreased adiposity, and insulin hypersensitivity in vivo. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5680-5. Epub 2007 Mar

Yuan H, Barnes KR, Weissleder R, Cantley L, Josephson L. Covalent reactions of wortmannin under physiological conditions. Chem Biol. 2007 Mar;14(3):321-8.

Taniguchi CM, Aleman JO, Ueki K, Luo J, Asano T, Kaneto H, Stephanopoulos G, Cantley LC, Kahn CR. The p85alpha regulatory subunit of phosphoinositide 3-kinase potentiates c-Jun N-terminal kinase-mediated insulin resistance. Mol Cell Biol. 2007 Apr;27(8):2830-40. Epub 2007 Feb 5.

Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Janne PA. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007 May 18;316(5827):1039-43. Epub 2007 Apr 26.

Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007 Jun 29;129(7):1261-74.

Chang JD, Sukhova GK, Libby P, Schvartz E, Lichtenstein AH, Field SJ, Kennedy C, Madhavarapu S, Luo J, Wu D, Cantley LC. Deletion of the phosphoinositide 3-kinase p110{gamma} gene attenuates murine atherosclerosis. Proc Natl Acad Sci U S A. 2007 May 8;104(19):8077-82. Epub 2007 May 2.

Hutti JE, Madhavarapu S, Kelliher MA, Cantley LC. Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol Cell Biol. 2007 Sep;27(17):6012-25. Epub 2007 Jun 11.

Asara JM, Christofk HR, Freimark LM, Cantley LC. A label-free quantification method by MS/MS TIC compared to SILAC and spectral counting in a proteomics screen. Proteomics. 2008 Mar;8(5):994-9.

Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature. 2008 Mar 13;452(7184):181-6.

Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008 Mar 13;452(7184):230-3.

Hill JW, Williams KW, Ye C, Luo J, Balthasar N, Coppari R, Cowley MA, Cantley LC, Lowell BB, Elmquist JK. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest. 2008 Apr 1; [Epub ahead of print]

Yuan TL, Choi HS, Matsui A, Benes C, Lifshits E, Luo J, Frangioni JV, Cantley LC. Class 1A PI3K regulates vessel integrity during development and tumorigenesis. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9739-44. Epub 2008 Jul 10.

Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008 Sep;118(9):3065-74.

Shaywitz AJ, Courtney KD, Patnaik A, Cantley LC. PI3K enters beta-testing. Cell Metab. 2008 Sep;8(3):179-81.






			Lewis Cantley, Ph.D. Signal Transduction Pathways that Control Metabolism The major research objective of this laboratory is to understand the biochemical pathways that regulate normal mammalian cell growth and the defects that cause cell transformation. More than 20 years ago this laboratory discovered phosphoinositide 3-Kinase (PI3K) as an enzyme that co-purified with a variety of oncoproteins (Whitman et al., 1988). Subsequent research from this laboratory and other laboratories showed that PI3K activation is critical for oncogene-mediated cell transformation, as well as for insulin-dependent stimulation of glucose uptake and metabolism. Further work from this laboratory and other laboratories revealed that lipid products of PI3K directly activate the AKT/PKB protein kinase to provide a cell survival signal (Franke et al., 1997). This discovery, as well as subsequent discoveries from other laboratories that human cancers frequently have activating mutations in PI3K genes and/or inactivating mutations in the PTEN gene (encoding a phosphatase that degrades PI3K lipid products) stimulated pharmaceutical companies to develop PI3K pathway inhibitors for cancer therapy. The Cantley laboratory is currently utilizing mouse models, genetically engineered with mutations in the PI3K pathway, to investigate opportunities for therapeutic intervention in diseases that result from defects in the PI3K pathway (Fruman et al., 1999, 2000; Ueki et al., 2002A, 2002B, 2003; Brachmann et al., 2005A, 2005B; Luo et al., 2005, Yuan et al., 2008; Engelman et al., 2008). Recent studies from this laboratory have revealed that growth factors, through activation of PI3K and other signaling pathways, cause major changes in cellular metabolism that are critical for the growth of cancer cells. Of particular interest, cancer cells invariably utilize an embryonic form of pyruvate kinase (PKM2) to channel glucose metabolites for optimal cell growth (Christofk et al., 2008A, 2008B). Ongoing studies are defining how oncogene transformation of cells alters the flux of metabolites such as glucose and glutamine and how these changes enhance cell growth and cell survival. Another major focus of this laboratory is the structural basis for specificity in protein/protein interactions in signal transduction cascades that control cell growth and survival. In particular, this laboratory has focused on the mechanism by which protein phosphorylation can control the assembly of signaling complexes. A novel oriented peptide library technique was developed to determine optimal phosphopeptides for binding to various protein domains (Songyang et al., 1993). This technique was subsequently modified to determine optimal substrates for protein kinases (Songyang et al., 1994, 1995, 1996; Hutti et al., 2004). The identification of optimal peptides has facilitated the determination of the structure of protein-peptide complexes and explained how specificity in signaling is maintained (Yaffe et al., 1997A, 1997B; Elia et al., 2003A, 2003B; Benes et al., 2005). These studies have also led to a bioinformatics approach (Scansite) for predicting sites of protein phosphorylation and protein interaction from primary sequences (Yaffe et al., 2001; Obenauer et al., 2003). References: Zheng B, Cantley LC. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):819-22. Epub 2007 Jan 4. Holt LJ, Hutti JE, Cantley LC, Morgan DO. Evolution of Ime2 phosphorylation sites on Cdk1 substrates provides a mechanism to limit the effects of the phosphatase Cdc14 in meiosis. Mol Cell. 2007 Mar 9;25(5):689-702. Hurov JB, Huang M, White LS, Lennerz J, Choi CS, Cho YR, Kim HJ, Prior JL, Piwnica-Worms D, Cantley LC, Kim JK, Shulman GI, Piwnica-Worms H. Loss of the Par-1b/MARK2 polarity kinase leads to increased metabolic rate, decreased adiposity, and insulin hypersensitivity in vivo. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5680-5. Epub 2007 Mar Yuan H, Barnes KR, Weissleder R, Cantley L, Josephson L. Covalent reactions of wortmannin under physiological conditions. Chem Biol. 2007 Mar;14(3):321-8. Taniguchi CM, Aleman JO, Ueki K, Luo J, Asano T, Kaneto H, Stephanopoulos G, Cantley LC, Kahn CR. The p85alpha regulatory subunit of phosphoinositide 3-kinase potentiates c-Jun N-terminal kinase-mediated insulin resistance. Mol Cell Biol. 2007 Apr;27(8):2830-40. Epub 2007 Feb 5. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Janne PA. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007 May 18;316(5827):1039-43. Epub 2007 Apr 26. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007 Jun 29;129(7):1261-74. Chang JD, Sukhova GK, Libby P, Schvartz E, Lichtenstein AH, Field SJ, Kennedy C, Madhavarapu S, Luo J, Wu D, Cantley LC. Deletion of the phosphoinositide 3-kinase p110{gamma} gene attenuates murine atherosclerosis. Proc Natl Acad Sci U S A. 2007 May 8;104(19):8077-82. Epub 2007 May 2. Hutti JE, Madhavarapu S, Kelliher MA, Cantley LC. Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol Cell Biol. 2007 Sep;27(17):6012-25. Epub 2007 Jun 11. Asara JM, Christofk HR, Freimark LM, Cantley LC. A label-free quantification method by MS/MS TIC compared to SILAC and spectral counting in a proteomics screen. Proteomics. 2008 Mar;8(5):994-9. Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature. 2008 Mar 13;452(7184):181-6. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008 Mar 13;452(7184):230-3. Hill JW, Williams KW, Ye C, Luo J, Balthasar N, Coppari R, Cowley MA, Cantley LC, Lowell BB, Elmquist JK. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest. 2008 Apr 1; [Epub ahead of print] Yuan TL, Choi HS, Matsui A, Benes C, Lifshits E, Luo J, Frangioni JV, Cantley LC. Class 1A PI3K regulates vessel integrity during development and tumorigenesis. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9739-44. Epub 2008 Jul 10. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008 Sep;118(9):3065-74. Shaywitz AJ, Courtney KD, Patnaik A, Cantley LC. PI3K enters beta-testing. Cell Metab. 2008 Sep;8(3):179-81.