However, existing models provide an incomplete picture of the transitions at the level of dimers as well as higher order spatial organization in a cellular context. The signaling by the kinase active but ligand binding incompetent ERBB2 and kinase-deficient but ligand-binding ERBB3 receptor is a central aspect from which many of our research projects branch of. The premise of our work is that these additional levels of control shift in the context of cellular transformation and that they can be subject to external modulation resulting in altered signaling outcomes, both quantitatively and qualitatively. To this end, we focus on the direct biochemical and molecular dissection of these additional control levels, the development of tools suitable for the study of these poorly understood and highly dynamic level of molecular organization, as well as ways to deliberately perturb and redirect ERBB signaling at levels that are currently not being targeted therapeutically.

Projects include:

Redirecting the outcome of ERBB signaling through receptor targeted intervention: Based on observations that ERBB2 signaling in a specific context can be growth inhibitory, we try to better understand the molecular parameters that qualitatively alter the outcome in signaling and to learn how we can enforce these alternative outcomes in cancer cells. Dissecting and influencing the membrane microenvironment of ERBB receptors: The immediate lipid membrane microenvironment of ERBB receptors plays a significant and poorly understood role in the control of signaling. Current studies focus on understanding differences in the microenvironment of ERBB2 and ERBB3 and the role that perturbations of the lipid profile may have on the modulation of “normal” signaling and drug resistance phenomena. Identification of receptor specific interaction partners during receptor degradation and maturation: Although catalytically impaired, ERBB3 is emerging as a key player in cancer due to its strong ability to activate the PI3K/Akt pro-survival signaling pathway. Much of this adaptation occurs at the level of posttranslational control. We are studying the mechanisms that are involved in the regulation of steady state levels of ERBB3, the mechanisms of ERBB3 ubiquitination, and receptor maturation. The goal is to identify cofactors in the posttranslational control of ERBB3 that represent suitable drug targets.

Aptamers as inhibitors, delivery vehicles and imaging probes: A considerable focus for our work is in vitro selected nucleic-acid aptamers. Aptamers have antibody-like affinity against their selected targets but are 1/10 the size of antibodies. The option of fully synthetic production and relative easy of chemical modification provides a broad spectrum of applications. Those include the development of drug delivery vehicles, diagnostic probes that may discern both receptor levels and the activation states of receptors, as well as probes that can report on the microenvironment of receptors in live cells.

Live cell targeting of ERBB3 (green) with aptamers (100nM, red). (DAPI staining of transfected and non-transfected CHO cells)