Kevan M. Shokat, PhD

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Kevan M. Shokat, PhD

Professor and Chair, Department of Cellular and Molecular Pharmacology, UCSF; Professor, Department of Chemistry, UC Berkeley; Investigator, Howard Hughes Medical Institute

kevan.shokat@ucsf.edu

Phone: (415) 514-0472 (voice)
Box 2280, UCSF
San Francisco, CA 94143-2280

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Cancer Center Membership

Program Member » Developmental Therapeutics» Cancer Genetics

Research Summary

Research in my laboratory is focused on the discovery of new chemical based tools to decipher cellular signaling networks with an emphasis on protein kinases and more recently, GTPases. The analysis of signal transduction pathways has proven challenging using the traditional tools of biochemistry, genetics, and chemistry. Biochemical approaches are often limited in utility because signaling networks span from the cell surface to the control of transcription and translation, confounding reconstitution efforts from purified proteins. Genetic approaches allow specific perturbation of single components in an intact cell or organism, yet are often confounded by the emergent properties of signaling cascades. Chemical and pharmacological approaches enable rapid, reversible, and graded (dose-dependent) inactivation of single components in intact cells or organisms. Unfortunately, highly selective chemical probes (agonists, antagonists, traceable substrates, etc.) of protein kinases are difficult to develop because the 500 protein kinases share highly homologous ATP binding pockets. My laboratory has solved this fundamental problem for the largest family of enzymes in the human genome, protein kinases, by development of a strategy based on a combination of protein engineering and organic synthesis. We have termed this approach chemical genetics.

Education

Reed College (Portland, Oregon), B.A., 1986, Chemistry
UC Berkeley (Berkeley, California), Ph.D., 1991, Organic Chemistry


Professional Experience

  • 1986-1991
    (Advisor: Prof. Peter G. Schultz, UC Berkeley): Design and synthesis of haptens for the generation of catalytic antibodies. Thesis Title: New Routes to Catalytic Antibodies.
  • 1992-1994
    (Advisor: Prof. Christopher C. Goodnow, Stanford University): Investigation of mechanisms of immune self-tolerance in transgenic mice.
  • 1994-1998
    Assistant Professor of Chemistry and Molecular Biology, Princeton University
  • 1998-1999
    Associate Professor of Chemistry and Molecular Biology, Princeton University
  • 1999-2002
    Associate Professor of Cellular and Molecular Pharmacology, University of California, San Francisco
  • 1999-2002
    Associate Professor of Chemistry, University of California, Berkeley
  • 2001-present
    Professor of Cellular and Molecular Pharmacology, University of California, San Francisco
  • 2002-present
    Professor of Chemistry, University of California, Berkeley
  • 2004-present
    Vice-Chairman of Cellular and Molecular Pharmacology, UCSF
  • 2004-present
    Investigator, Howard Hughes Medical Institute

Honors & Awards

  • 1986
    Phi Beta Kappa - Reed College
  • 1986-1987
    UC Berkeley Regents Fellowship
  • 1989-1990
    UC Berkeley University Fellowship
  • 1992-1994
    Life Sciences Research Foundation Postdoctoral Fellow
  • 1995-1997
    NSF Early Career Development Award
  • 1996-2000
    Pew Scholar in the Biomedical Sciences
  • 1997-1998
    Glaxo-Wellcome Scholar in Organic Chemistry
  • 1997-2000
    Searle Scholar
  • 1997-2000
    Cottrell Scholar
  • 1999-2001
    Alfred P. Sloan Research Fellow
  • 2001
    Protein Society Young Investigator Award
  • 2002
    Eli Lilly Award in Biological Chemistry

Selected Publications

  1. P-TEFb regulation of transcription termination factor Xrn2 revealed by a chemical genetic screen for Cdk9 substrates. Genes Dev. 2016 Jan 1; 30(1):117-31.
    View on PubMed
  2. Inhibition of Calcium-Dependent Protein Kinase 1 (CDPK1) In Vitro by Pyrazolopyrimidine Derivatives Does Not Correlate with Sensitivity of Cryptosporidium parvum Growth in Cell Culture. Antimicrob Agents Chemother. 2015; 60(1):570-9.
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  3. Discovery and functional characterization of a neomorphic PTEN mutation. Proc Natl Acad Sci U S A. 2015 Oct 26.
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  4. Identification of AMPK Phosphorylation Sites Reveals a Network of Proteins Involved in Cell Invasion and Facilitates Large-Scale Substrate Prediction. Cell Metab. 2015 Nov 3; 22(5):907-21.
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  5. Small molecule inhibition of Csk alters affinity recognition by T cells. Elife. 2015; 4.
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  6. Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1. Bioorg Med Chem. 2015 Sep 1; 23(17):5483-8.
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  7. SR protein kinases promote splicing of nonconsensus introns. Nat Struct Mol Biol. 2015 Aug; 22(8):611-7.
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  8. WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons. Sci Signal. 2015; 8(383):ra65.
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  9. Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic. Elife. 2015; 4.
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  10. Downregulation of MYCN through PI3K Inhibition in Mouse Models of Pediatric Neural Cancer. Front Oncol. 2015; 5:111.
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  11. Differential genetic interactions of yeast stress response MAPK pathways. Mol Syst Biol. 2015; 11(4):800.
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  12. The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner. Biochem J. 2015 Apr 1; 467(1):47-62.
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  13. Structure of the Human Autophagy Initiating Kinase ULK1 in Complex with Potent Inhibitors. ACS Chem Biol. 2015 Jan 16; 10(1):257-61.
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  14. Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy. Elife. 2014; 3.
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  15. Radiotherapy followed by aurora kinase inhibition targets tumor-propagating cells in human glioblastoma. Mol Cancer Ther. 2015 Feb; 14(2):419-28.
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  16. Targeting osteosarcoma. Proc Natl Acad Sci U S A. 2014 Dec 23; 111(51):18100-1.
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  17. Linking Tumor Mutations to Drug Responses via a Quantitative Chemical-Genetic Interaction Map. Cancer Discov. 2015 Feb; 5(2):154-67.
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  18. MST3 Kinase Phosphorylates TAO1/2 to Enable Myosin Va Function in Promoting Spine Synapse Development. Neuron. 2014 Dec 3; 84(5):968-82.
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  19. Reflecting on the past and looking forward to the future of bridging chemistry and biology. Chem Biol. 2014 Sep 18; 21(9):1035-6.
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  20. The proprotein convertase subtilisin/kexin type 9 (PCSK9) active site and cleavage sequence differentially regulate protein secretion from proteolysis. J Biol Chem. 2014 Oct 17; 289(42):29030-43.
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