Protein-tyrosine Phosphatases and PTEN: the Work of Jack E. Dixon
Year: 2006
Type: article
Abstract: Evidence for protein-tyrosine-phosphatase catalysis proceeding via a cysteine-phosphate intermediate.Journal of Biological ChemistryVol. 266Issue 26PreviewA recombinant protein-tyrosine-phosphatase has been expressed in Escherichia coli and purified to a single band by sodium dodecyl sulfate-polyacrylamide gel electrophoresis using affinity chromatography. When the phosphatase was allowed to react with 32P-labeled substrates and then rapidly denaturated, a 32P-labeled phosphoprotein could be visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Transient formation of a 32P-labeled phosphoprotein was observed, and the 32P-labeled protein disappeared as substrate was consumed. Full-Text PDF Open Access Evidence for Protein-tyrosine-phosphatase Catalysis Proceeding via a Cysteine-Phosphate Intermediate (Guan, K. L., and Dixon, J. E. (1991) J. Biol. Chem. 266, 17026–17030) The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate (Maehama, T., and Dixon, J. E. (1998) J. Biol. Chem. 273, 13375–13378) Jack E. Dixon was born and raised in Nashville, Tennessee. He earned his undergraduate degree from the University of California Los Angeles in 1966 and his doctorate in chemistry from the University of California Santa Barbara in 1971. He did a postdoctoral fellowship at the University of California San Diego from 1971 to 1973 with Nathan O. Kaplan, who will be the subject of a future Journal of Biological Chemistry (JBC) Classic. Dixon then went to Purdue University, joining the faculty of the Department of Biochemistry, and remained there for 18 years. He was named Distinguished Professor of Biochemistry in 1986. In 1991, Dixon moved to Ann Arbor, Michigan, to become Chair of the Department of Biological Chemistry at the University of Michigan. He held the Minor J. Coon Professorship and became co-director of Michigan's Life Sciences Institute in 2001. In 2003, he returned to California to become Dean of Scientific Affairs at UCSD. Early in his career, Dixon was a leader in research on the biosynthesis and post-translational processing of polypeptide hormones. He adopted the tools of molecular biology as they became available in the late 1970s, and his laboratory was among the first to use a synthetic oligonucleotide to identify and clone cDNAs encoding peptide hormones such as somatostatin, cholecystokinin, and neuropeptide Y. He subsequently became a pioneer in the structure and function of the protein-tyrosine phosphatases and their roles in cellular signaling. The protein-tyrosine phosphatases (PTPases) are a diverse group of enzymes that participate in cellular signaling by regulating the reversible addition of phosphate to tyrosine residues. Dixon cloned, expressed, and characterized a number of PTPases and showed that this entire family of enzymes proceeds via a unique phosphoenzyme intermediate. This research is the focus of the JBC Classics reprinted here. In the Classic paper, Dixon uses purified recombinant protein-tyrosine phosphatase to explore the catalytic mechanism employed by the enzyme. By allowing the phosphatase to react with 32P-labeled substrates and then rapidly denaturing the enzyme, a 32P-labeled phosphoprotein could be visualized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Using site-directed mutagenesis, Dixon showed that Cys215 was essential for enzyme activity. He also determined that the cysteine residue forms a covalent thiol phosphate bond. It was later shown that the entire family of phosphatases used this same catalytic mechanism. In the late 1990s, Dixon turned his focus to the tumor suppressor PTEN, which shares sequence identity with the family of PTPases. As reported in the second JBC Classic, Dixon identified PTEN′s substrate. Surprisingly, the substrate was not a protein, but a phospholipid, phosphatidylinositol 3,4,5-trisphosphate. This was the first reported example of a PTPase that functioned to dephosphorylate a lipid second messenger, and it also established the biological function of PTEN. The discovery explained why and how PTEN functioned as a tumor suppressor gene, and this in turn suggested which signaling pathway could be targeted in treating cancers where there was a loss of this gene. Dixon remains at UCSD as Professor of Pharmacology, Cellular and Molecular Medicine, Chemistry, and Biochemistry. He recently identified most, if not all, of the PTPases in the human genome. There appear to be 107 genes in the human genome that encode members of the PTP families. Currently he is focusing on the role of PTPase in guiding neuronal axons to specific targets. Dixon was recently appointed Vice President and Chief Scientific Officer of the Howard Hughes Medical Institute (HHMI). He has authored or co-authored more than 250 scientific articles. He served as the president of the American Society for Biochemistry and Molecular Biology in 1996 and is a member of the Institute of Medicine, the American Academy of Arts and Sciences, and the National Academy of Sciences. He was named the Michigan Scientist of the Year in 1994. In 1997, he received the University of Michigan Distinguished Faculty Lectureship Award in Biomedical Research, in 1999 he was chosen as the University of Michigan Henry Russel Lecturer, and in 2005 he received the American Society for Biochemistry and Molecular Biology Merck award.
Source: Journal of Biological Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1935449888