Binks Wattenberg, PhD
Research Program
Molecular Targets
Education B.A., Cornell University, Ithaca, New York, Biology, 1971-1976 1992-1995 1996-2002 2002-present
Ph.D., Washington University, St. Louis, Missouri, Biochemistry, 1976-1981
Post-Doctoral Fellowship, Standford University, Stanford, California, Biochemistry, 1981-1985
Research and Professional Experience
1986-1992
Research Scientist, The Upjohn Company, Kalamazoo, Michigan
Senior Research Scientist, The Upjohn Company, Kalamazoo, Michigan
Head, Molecular-Cell Biology Laboratory, The Hanson Centre for Cancer Research, Adelaide, South Australia
Associate Professor, Dept. of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
Selected Awards and Professional Honors
1996-1998
Florey Fellow, Royal Adelaide Hospital, Adelaide, South Australia
1996-1998
State Representative, Australia and New Zealand Society for Cell and Developmental Biology
1998
Principal Organizer, Hanson Symposium Satellite Meeting
1998
Organizing Committee, Australia and New Zealand Society for Cell and Developmental Biology
1999
Symposium Chair, Australian Meeting for Biochemistry and Molecular Biology
2000
Principal Organizer, Hanson Symposium Satellite Meeting
2002
Symposium Chair, International Conference on Second Messengers and Phosphoproteins
2003 - Present
Member, American Heart Association Study Section-Cell Metabolism and Physiology
2005 - Present
Chair, American Heart Association Study Section-Cell Metabolism and Physiology
Research Interest
Biological Membranes in Intracellular Signaling
My laboratory is engaged in two major projects, one involving the lipid signaling enzyme Sphingosine Kinase and the second to understand the trafficking and function of the so-called “Tail-Anchored” proteins.
Sphingosine-kinase: A Lipid Signalling Enzyme
Sphingosine-phosphate has recently gained considerable attention as both an intracellular second messenger and an extracellular ligand for a novel group of receptors. Its signaling functions have been associated with a variety of critical cellular processes including cell survival and proliferation, cell migration, and expression of inflammatory adhesion molecules. The key regulatory step which determines levels of sphingosine-phosphate in the cell is the activity of sphingosine-kinase. Sphingosine-kinase activity is regulated by an interesting array of extracellular ligands including tumor necrosis factor, interleukin-1, and growth factors. Our recent studies have demonstrated that the signaling function of sphingosine kinase depends as much on where in the cell the enzyme is located as its degree of enzymatic activation. We are currently exploring how changes in localization of this critical signaling enzyme occur and why localization is such an important aspect of its signaling function.
Trafficking of Tail-Anchored Proteins
A substantial class of proteins are anchored by C-terminal membrane anchors to intracellular membranes. These are known as tail-anchored proteins. Prominent among these are the Bcl-2 family of apoptosis-related proteins, and the SNARE class of vesicle targeting proteins. Despite this importance, little is known about the mechanism that targets these proteins to their correct locations. The membrane anchor and flanking sequences also are responsible for targeting during membrane insertion and so are classified as signal/anchor sequences. The two known sites of insertion of these proteins are the endoplasmic reticulum and mitochondria. We have focused on the mechanism targeting these proteins to the mitochondrial outer membrane.We believe that the targeting of these proteins is the result of the interaction between a unique conformational structure of the signal/anchor sequences, molecular chaperones, and a membrane targeting and insertion apparatus in the mitochondrial outer membrane. We will are testing this hypothesis by determining the sequence and 3-dimensional structure of functional signal/anchors, identifying molecular chaperones that interact with those sequences, and identifying components of the mitochondrial targeting machinery.
Publications Wattenberg BW, Silbert DF. Sterol partitioning among intracellular membranes. Testing a model for cellular sterol distribution. J Biol Chem 258:2284-9, 1983 Wattenberg BW, Rothman JE. Multiple cytosolic components promote intra-Golgi protein transport. Resolution of a protein acting at a late stage, prior to membrane fusion. J Biol Chem 261:2208-13, 1986 Wattenberg BW, Balch WE, Rothman JE. A novel prefusion complex formed during protein transport between Golgi cisternae in a cell-free system. J Biol Chem 261:2202-7, 1986 Wattenberg BW, Hiebsch RR, Lecureux LW, White MP. Identification of a 25 kD protein from yeast cytosol which operates in a prefusion step of vesicular transport between the compartments of the Golgi. J Cell Biol 110:947-54, 1990 Wattenberg BW. Glycolipid and glycoprotein transport through the Golgi complex are similar biochemically and kinetically. Reconstitution of glycolipid transport in a cell free system. J Cell Biol 111:421-8, 1990 Hiebsch RR, Raub TJ, Wattenberg BW. Primaquine blocks transport by inhibiting the formation of functional transport vesicles. Studies in a cell free assay of protein transport through the Golgi. J Biol Chem 266:20323-8, 1991 Hiebsch RR, Wattenberg BW. Vesicle fusion in protein transport through the Golgi in vitro does not involve long-lived prefusion intermediates. A reassessment of the kinetics of transport as measured by glycosylation. Biochemistry 31:6111-8, 1992 Wattenberg BW, Raub TJ, Hiebsch RR, Weidman PJ. The activity of Golgi transport vesicles depends on the presence of the N-ethylmaleimide sensitive factor (NSF) and a soluble NSF attachment protein (SNAP) during vesicle formation. J Cell Biol 118:1321-32, 1992 Fayos BE, Wattenberg BW. Regulated exocytosis in vascular endothelial cells can be triggered by intracellular guanine nucleotides and requires a hydrophobic, thiol-sensitive component. Endothelia 5:339-50, 1997 Isenmann S, Khew-Goodall Y, Gamble J, Vadas M, Wattenberg BW. A splice-isoform of vesicle-associated membrane protein-1 (VAMP-1) contains a mitochondrial targeting signal. Mol Biol Cell 9:1649-60, 1998 Lan L, Isenmann S, Wattenberg BW. Mitochondrial targeting of carboxy-terminally anchored protein is specific and saturable, but independent of ATP and cytosolic factors. Biochem J 349:611-21, 2000 Pitson SM, Moretti PAB, Zebol JR, Xia P, Gamble JR, Vadas MA, D’Andrea RJ, Wattenberg BW. Expression of a catalytically inactive sphingosine kinase mutant blocks agonist-induced sphingosine kinase activation: a dominant-negative sphingosine kinase. J Biol Chem 275:33945-50, 2000 Xia P, Gamble JR, Wang L, Pitson SM, Moretti PAB, Wattenberg BW, D’Andrea RJ, Vadas MA. Sphingosine kinase acts like an oncogenes. Current Biol 10:1527-30, 2000
Pitson SM, D’Andrea RJD, Vandeleur L, Moretti PAB, Xia P, Gamble JR, Vadas MA, Wattenberg BW. Human sphingosine kinase: purification, molecular cloning, and characterization of the native and recombinant enzymes. Biochem J 350:429-41, 2001