American Cancer Society Professor
Molecular and Cell Biology Laboratory
Renato Dulbecco Chair
Tony Hunter, a Professor in the Molecular and Cell Biology Laboratory and Director of the Salk Institute Cancer Center, studies how cell growth and division are regulated, and how mutations in genes that control growth lead to cancer. His group has made significant contributions in the area of signal transduction, elucidating how signals that stimulate or inhibit proliferation are transmitted within a cell.
In 1979, his group discovered that phosphate can be attached to tyrosine residues in proteins. This seminal discovery opened the door to the study of tyrosine kinases and their role in signal transduction, and in cell proliferation and development, as well as to their role in cancer and other human diseases. This knowledge already has resulted in the development of selective tyrosine kinase inhibitors that provide a new approach to cancer treatment.
His current efforts are aimed at elucidating how post-translational modification of proteins by phosphorylation, ubiquitylation, and sumoylation is used to regulate cell proliferation and cell cycle checkpoint activation in response to DNA damage. His recent work has highlighted crosstalk between phosphorylation and ubiquitylation, and between sumoylation and ubiquitylation in the control of cell signaling pathways, and in particular has defined the role of SUMO-targeted E3 ubiquitin ligases, such as RNF4 family ligases, that ubiquitylate sumoylated proteins leading to their degradation. His group has also defined a role for ubiquitylation in lifespan determination in C. elegans, characterized the consequences of somatic mutations in protein kinases such as DAPK3 in carcinogenesis, and has recently developed antibody reagents for studying histidine phosphorylation.
"The goal of our group is to elucidate signal transduction mechanisms utilizing protein phosphorylation/dephosphorylation, ubiquitylation, and sumoylation and to investigate how these processes regulate cell proliferation, growth control and the cell cycle. Ultimately, we want to use this information to uncover how dysregulation of such post-translational modifications is involved in cancer."
Protein kinases are key cellular enzymes; they attach phosphates to other proteins in the cell and thereby regulate their activities. This process, which is known as phosphorylation, is reversed by a second type of enzyme that removes the phosphate. Phosphorylation therefore acts as a molecular on/off switch. The human genome encodes nearly 540 different protein kinases, making them among the most abundant and important types of gene products.
One major function of protein phosphorylation is to control cell proliferation in response to external signals. A hallmark of cancer cells is that they continue to proliferate even in the absence of external signals to grow. In many cases, this is due to genetic changes that result in a protein kinase being continuously active instead of being toggled on and off in response to signals. Kinases that add phosphate to the amino acid tyrosine in proteins are particularly important cancercausing "oncoproteins," and a number of new cancer drugs are designed to block these rogue enzymes. However, kinases that add phosphates to the amino acids serine or threonine in proteins also play roles in cancer. Recent efforts to sequence entire tumor genomes have revealed that many types of protein kinases sustain mutations in cancer, including numerous ones that were not previously known to be involved.
Hunter and his team have analyzed the consequences of mutations in some of these cancer mutant kinases in the hope that they might identify new cancer drug targets. For one kinase that phosphorylates serine and threonine, known as death-associated protein kinase 3 or DAPK3, they found that the cancer mutations actually cause a decrease in the ability of the kinase to add phosphate to proteins. This unexpected discovery suggests a new model in which DAPK3 normally acts to rein in the growth of cells, whereas in cancer cells this "suppressor" activity has been lost through inactivating mutations. Thus, DAPK3 would not be a target for inhibitor drugs. Nevertheless, other mutant kinases emerging from sequencing studies may prove to be good targets, and Hunter's group is continuing to study cancer mutant kinases in the hope that unlocking their secrets will lead to better cancer therapies.
Back row, left to right:
Mike French, Justin Zimmermann
Front row, left to right:
Brandon Lamarche, Huaiyu Sun, Andrea Carrano, Megan Lambert, Yu Shi, Jill Meisenhelder, Lorena Puto, Tony Hunter, Natalie Luhtala, Suzy Simon, Xinde Zheng, Aaron Aslanian, Zheng Wang, Hui Ma
Salk News Releases
Pedal the Cause funds local ground-breaking cancer research with inaugural grant awards
May 29, 2014
American Association for Cancer Research appoints Salk scientists to inaugural class of fellows
March 25, 2013
What can the water monster teach us about tissue regeneration in humans?
September 25, 2012
Salk Institute Hosts Cell Cycle Symposium - Discussions that Change Lives
June 9, 2011
Salk Institute cancer researcher Tony Hunter named to Frederick W. and Joanna J. Mitchell Chair
March 2, 2010
Mobilizing the repair squad: Critical protein helps mend damaged DNA
December 24, 2009
Chemotherapy resistance: Checkpoint protein provides armor against cancer drugs
August 31, 2009
Climbing the ladder to longevity: critical enzyme pair identified
June 24, 2009
Breast cancer cells have to learn to walk before they can run
January 2, 2008
Get in Touch First
October 30, 2007
Tony Hunter receives Robert. J. and Claire Pasarow Award for Cancer Research
May 22, 2007
Distinguishing friend from foe in the battle against cancer
September 11, 2006
Genetically modified mice are resistant to obesity despite a high fat diet
February 7, 2006
Molecular 'zipcode' guides nerves to correct places in body
April 7, 2005
Salk Scientist who discovered cancer \'switch\' awarded the Wolf Prize in Medicine
January 14, 2005
Salk Scientist Who Revolutionized Cancer Research Awarded Horwitz Prize
December 3, 2004
Salk Institute Scientist Tony Hunter Named to Institute of Medicine
November 8, 2004
Hunter Receives Two Major Cancer Awards
March 2, 2004
Salk Researchers Ranked in Top 25 of Scientific Citations Worldwide
September 29, 2003
Missing Enzyme Found to Lead to Alzheimer?s Disease Symptoms
July 31, 2003
Salk Institute and SUGEN Scientists Map 'Human Kinome'
December 5, 2002
Potential Male Contraceptive Target Discovered by Salk Scientists
January 31, 2000
Ma, H., Han, B.K., Guaderrama, M., Aslanian, A., Yates III, J.R., Hunter, T., and Wittenberg, C. 2014. Psy2 targets PP4 to dephosphorylate Mth1 thereby antagonizing PKA to repress glucose transporter genes. Mol. Cell. Biol. 34:452-463.
Carrano AC, Dillin A and Hunter T. 2014. A Krüppel-like factor downstream of the E3 ligase WWP-1 mediates dietary-restriction-induced longevity in Caenorhabditis elegans. Nat Commun. May 8;5:3772. doi: 10.1038/ncomms4772.
Hunter T. 2014. The genesis of tyrosine phosphorylation. Cold Spring Harb Perspect Biol. May 1;6(5). pii: a020644. doi: 10.1101/cshperspect.a020644.
Ma L, Aslanian A, Sun H, Jin M, Shi Y, Yates JR 3rd and Hunter T. 2014. Identification of SUMO Substrates with Diverse Functions Using the Xenopus Egg Extract System. Mol Cell Proteomics. 2014 May 5.
Aslanian A, Yates JR 3rd and Hunter T. 2014. Mass spectrometry-based quantification of the cellular response to methyl methanesulfonate treatment in human cells. DNA Repair (Amst). 2014 Mar;15:29-38. doi: 10.1016/j.dnarep.2013.12.007. Epub 2014 Jan 22.
Zhang Y and Hunter T. 2014. Roles of Chk1 in cell biology and cancer therapy. Int J Cancer. 2014 Mar 1;134(5):1013-23. doi: 10.1002/ijc.28226. Epub 2013 May 28. Review.
Zheng X and Hunter T. 2013. Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism. Cell Res. 2013 Jul;23(7):886-97. doi: 10.1038/cr.2013.66. Epub 2013 May 14.
Yang,W., Xia, Y. Hawke, D., Li, X., Liang, J., Aldape, K., Hunter, T., Yung, W.K.A., and Lu, Z.. 2012. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 150:685-696.
Zhang, Q.C., Petrey, D., Deng, L., Qiang. L., Shi, Y., Thu, C. A., Bisikirska, B., Lefebvre, C., Accili, D., Hunter, T., Maniatis, T. Califano, A., and Honig, B. 2012. Structure-based prediction of protein-protein interactions on a genome-wide scale. Nature 490:556-560.
Sun H and Hunter T. 2012. Poly-small ubiquitin-like modifier (PolySUMO)-binding proteins identified through a string search. J Biol Chem. 2012 Dec 7;287(50):42071-83. doi: 10.1074/jbc.M112.410985. Epub 2012 Oct 18.
Zhu W, Kuo D, Nathanson J, Satoh A, Pao GM, Yeo GW, Bryant SV, Voss SR, Gardiner DM and Hunter T. 2012. Retrotransposon long interspersed nucleotide element-1 (LINE-1) is activated during salamander limb regeneration. Dev Growth Differ. 2012 Sep;54(7):673-85. doi: 10.1111/j.1440-169X.2012.01368.x. Epub 2012 Aug 23.
Hunter T. 2012. Why nature chose phosphate to modify proteins. Philos Trans R Soc Lond B Biol Sci. 2012 Sep 19;367(1602):2513-6. doi: 10.1098/rstb.2012.0013. Review.
Wang Z, Shah OJ and Hunter T. 2012. The transcriptional coactivators p/CIP and SRC-1 control insulin resistance through IRS1 in obesity models. PLoS One. 2012;7(7):e36961. doi: 10.1371/journal.pone.0036961. Epub 2012 Jul 31.
Zhu W, Pao GM, Satoh A, Cummings G, Monaghan JR, Harkins TT, Bryant SV, Randal Voss S, Gardiner DM and Hunter T. 2012. Activation of germline-specific genes is required for limb regeneration in the Mexican axolotl. Dev Biol. 2012 Oct 1;370(1):42-51. doi: 10.1016/j.ydbio.2012.07.021. Epub 2012 Jul 27.
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Awards and Honors
- Fellow of the Royal Society of London
- Member of the United States National Academy of Sciences
- Fellow of the American Academy of Arts and Sciences
- Institute of Medicine of the National Academies
- Member of the American Philosophical Society
- American Cancer Society Research Professorship
- General Motors Cancer Research Foundation Prize, 1994
- Gairdner Foundation International Award, 1994
- J. Allyn Taylor International Prize in Medicine, 2000
- Keio Medical Science Prize, 2001
- Sergio Lombroso Award in Cancer Research, 2003
- City of Medicine Award, 2003
- American Cancer Society Medal of Honor, 2004
- Kirk A. Landon-AACR Prize for Basic Cancer Research, 2004
- Prince of Asturias Award for Scientific and Technical Research 2004
- Louisa Gross Horwitz Prize, 2004
- Wolf Prize in Medicine, 2005
- Daniel Nathan's Memorial Award, 2006
- Robert J. and Claire Pasarow award for Cancer Research, 2006
- Clifford Prize for Cancer Research, 2007
- Lifetime Achievement in Cancer Research Award, Jefferson Kimmel Cancer Center, 2011
- Signal Transduction Society Honorary Medal, 2011
- Thomson-Reuters Citation Laureate, 2012
- Einstein Professor, Chinese Academy of Sciences, 2013
- Fellow, AACR Academy, 2013