Welcome to the Landgraf Lab Homepage! The main focus of our research are receptor tyrosine kinases with homology to the human EGF receptor (HER's or cErbB's). For humans, this family includes EGFR, ERBB2, ERBB3 and ERBB4. We are specifically interested how the outcome of receptor activation is influenced by the formation and modulation of higher order receptor clusters as well as alterations in the membrane microenvironment of the receptors. Receptor dimers, both homodimers or heterodimers, are at the core of signaling. However, while dimers are essential, they are not sufficient for activation. Different receptors in this family are capable of a variety of transient interactions with their ligands and with each other. Elevated expression levels, especially of ERBB2 are correlated with a number of solid tumor malignancies, but ERBB receptors are involved in a large range of cellular responses beyond enhanced proliferation, including differentiation and apoptosis.
We investigate the nature of ERBB interactions on a molecular level. Of particular interest to us are the molecular driving forces and the consequences of higher order receptor clustering events, that is complexes that go beyond receptor dimers. This is a complex and dynamic process involving multiple receptor interfaces. Receptor interactions can be both stabilized and destabilized by ligand binding. This creates a structural signaling context which is further modulated by the fact that ERBB receptors segregate into different membrane microdomains. Microcompartmentalization on the cell surface alters both the intrinsic properties of the receptors as well the complement of interaction partners.
Our characterization of receptor interactions and signaling control combines computational biology, biochemistry, and molecular & cell biology. Specific areas of interest are the dissection of receptor interfaces involved in clustering, the control of the intrinsic activation status of receptors in clusters, the visualization of clustering events and its regulation in a cellular setting, the dissection of the mechanisms that control constitutive turn-over of ERBB3 (which is unique in several key aspects of ERBB signaling (see science intro)), the role of raft like microdomains in ERBB2/ERBB3 signaling, and the use of in vitro selected nucleic acid aptamers as both prototype inhibitors of ERBB activation as well as activation state specific probes of ERBB function in live cells.
Ralf Landgraf, PhD
Assistant Professor
Department of Medicine, Division of Hematology-Oncology,
Dept. of Biological Chemistry &
Molecular Biology Institute
University of California, Los Angeles
Lab: Center for the Health Sciences (CHS) 52-054
Lab. Phone: (310) 825-8221
Office: Louis Factor Building 9-155
Phone: (310) 206-7239
FAX: (310) 825-6192
rlandgraf@mednet.ucla.edu