Frank Gertler, Ph.D.
Department of Biology
Associate Professor of Biology
Ph.D. in Oncology, 1992, University of Wisconsin - Madison
Research in the Gertler lab focuses on the relationship of cellular environmental response and cell motility. The lab uses genetic, cell biological and biochemical approaches to study the relationship of environmentally activated signal transduction networks and continual remodeling of the actin cytoskeleton necessary for cell movement. Many biological processes depend on cell motility ranging from development of neuronal tissue to invasion of cancer cells in tumorigenesis. By integrating multiple approaches, the Gertler lab is trying to understand the stimulatory mechanisms and the structural changes essential for guided cell movement.
Protein Networks Involved in Neuronal Migration
Early development of neuronal tissues in many organisms depends on the concerted regulation of cell motility. Migration of early neurons in mice to their appropriate location in the brain ensures proper development of synaptic connections. Using fluorescence and time-lapse microscopy of living cells, the lab investigates the migration of neurons and their growth cones -- actin-rich structures that guide developing axons and dendrites to their targets. In particular, they have identified proteins that localize to locations important for cell motility including focal adhesions, lammellipodia and filopodial tips, bind to actin monomers and affect actin cytoskeletal structures.
The Ena/Vasodilutor-stimulated phosphoprotein (VASP) family of actin-regulatory proteins function in a variety of cell types and organisms to regulate cell morphology and motility. Research in the lab has demonstrated that these proteins interact directly with growing actin filaments and antagonize actin capping. Mice deficient in one member of the family show subtle brain abnormalities whereas double mutants have severe deformation of the central nervous system. The Gertler lab is continuing to genetically manipulate other members of the family to understand their roles in the signal transduction network that leads to neuronal development.
In the case of AIDS therapy, we are using our understanding of protein
design to predict the interactions of drugs with proteins from the HIV virus.
The virus mutates so rapidly that a single line of therapy is often evaded
immediately. With knowledge of the mechanisms of drug binding, we can design
drug candidates that bind many of the mutant proteins that might escape conventional
therapy. This approach of developing universal therapies can be applied
to other areas, such as antibiotics or antibody therapeutics.
Actin-Regulatory Protein Motifs in Tumorigenesis
Using the knowledge gained through the study of Ena/VASP proteins in neuronal migration, the Gertler lab has identified domains within Ena/VASP, called EVH1 and EVH2, important for regulating cell motility. EVH1 is important for binding of proteins containing a specific prolinerich motif and EVH2 is the actin-binding domain. Interaction with the EVH1 domain allows for intracellular targeting of Ena/VASPproteins to receptor/signaling complexes. In their search of the proteome for these domains, the Gertler lab has identified new members of the signal network including lammellipodin (Lpd) that localizes to the leading edge of the cell membrane. In collaboration with the Yaffe lab, the Gertler lab demonstarted that a PH domain within Lpd binds to PI(3,4)P2, a phosphoinisotide produced in response to chemotactic stimulation. In addition, overabundance of Lpd increases the velocity of lamellipodia protrusion. The loss-offunction phenotype observed with Lpd is more severe than the loss of any one of the Ena/VASP proteins suggesting that Lpd regulates other effectors of the actin-cytoskeleton in addition to the Ena/VASP pathway.
- Bear, JE, Svitkina, TM, Krause , M, Schafer, DA,Loureiro, JJ, Strasser, GA, Maly, IV, Chaga, O, Cooper, JA, Borisy, GG and Gertler, FB.. Antagonism between Ena/VASP Proteins and Actin Filament Capping regulates Fibroblast Migration. Cell, 109: 509-521(2002).
- Lebrand C, Dent EW, Strasser GA, Lanier LM, Krause M, Svitkina TM, Borisy GG, Gertler FB. Critical role of Ena/VASP proteins for filopodia formation in neurons and in function downstream of netrin-1. Neuron. 2004 Apr 8;42(1):37-49
- Lafuente EM, van Puijenbroek AA, Krause M, Carman CV, Freeman GJ, Berezovskaya A, Constantine E, Springer TA, Gertler FB, Boussiotis VA. RIAM, an Ena/VASP and Profilin Ligand, Interacts with Rap1-GTP and Mediates Rap1-Induced Adhesion. Dev Cell. 2004 Oct;7(4):585-95.
- Krause M, Leslie JD, Stewart M, Lafuente EM, Valderrama F, Jagannathan R, Strasser GA, Rubinson DA, Liu H, Way M, Yaffe MB, Boussiotis VA, Gertler FB. Lamellipodin, an Ena/VASP Ligand, Is Implicated in the Regulation of Lamellipodial Dynamics. Dev Cell. 2004 Oct;7(4):571-83.
- Menzies AS, Aszodi A, Williams SE, Pfeifer A, Wehman AM, Goh KL, Mason CA, Fassler R, Gertler FB. Mena and vasodilator-stimulated phosphoprotein are required for multiple actin-dependent processes that shape the vertebrate nervous system. J Neurosci. 2004 Sep 15;24(37):8029-38.
Last Updated: April 9, 2008