Kathleen Van Craenenbroeck

2012 -

10% Professor University Gent, Department Physiology

90% Postdoctoral fellowship FWO (continuation position 2006 -…)  

2006 - 2013

Postdoctoral fellowship FWO

University Gent
"Interactions in the endoplasmatic reticulum, important in the biogenesis of the dopamine D4 receptor"

2003 - 2006

Postdoctoral fellowship IWT / Innogenetics

University Gent
"Pharmacological chaperones and the maturation of the dopamine D4 receptor"

2002 - 2003

Stay abroad: Postdoctoral fellowship

Centre for Addiction and Mental Health, University of Toronto, Canada

"Biogenesis of the dopamine D4 receptor"

2000 - 2002

BOF Postdoctoral fellowship

University Gent - VIB
"Searching for proteins interacting with the third intracellular loop of the dopamine D4 receptor"

1995 - 2000

PhD student, IWT-project / Janssen Research Foundation

University Gent - VIB
"Study of inducible systems for the heterologous gene expression of neurotransmitter receptors in mammalian cells."

Research Interests:

We started this research group several years ago, as partner of a collaboration with Janssen Research Foundation (Johnson and Johnson) focusing on the “Study of inducible systems for the heterologous gene expression of neurotransmitter receptors in mammalian cells”. This research delved with the development of pharmaca involved in the regulation of mood, social behavior, schizophrenia, etc. This topic stimulated us to start studying GPCR physiology and to investigate the signaling and regulation of some of these neurotransmitter receptors e.g. the dopamine D2-like receptors, the serotonin 5- HT7 receptor and the µ opioid receptor. This research can show the way to a better understanding of brain diseases and to the development of an improved and more specific therapy.

A first step to unravel a signaling pathway consisted of the identification of proteins that interact with the receptor of interest. We performed multiple yeast two-hybrid screenings and identified several important interacting proteins, which were/are studied in further detail.

In the future we will continue our research to obtain a better knowledge of GPCR physiology. The emphasis will be on the following two research topics:

  1. Investigation of the role of GPCR ubiquitination in signaling and regulation. Ubiquitination is a post-translational modification that targets proteins for degradation but can also regulate other cellular processes such as endocytosis, trafficking, DNA repair, etcetera. We are investigating ubiquitination of the dopamine D4 receptor (D4R). Several polymorphic variants of the D4R exist, which differ in the number of 16-amino acid repeats in the third intracellular loop of the receptor. The functional role of the receptor polymorphic region is not known but persons with the seven-repeat allele show a predisposition to develop Attention Deficit Hyperactivity Disorder (ADHD). We have identified a protein, KLHL12, which specifically interacts with this region and enhances ubiquitination of the D4R. Most studies have focused on the role of GPCR ubiquitination in receptor degradation; nevertheless, our experimental results gave clear evidence that KLHL12-mediated D4R ubiquitination does not lead to receptor degradation. Additionally, we are studying the influence of ubiquitination on receptor signaling.
  2. GPCR dimerization (as described in the project proposal)

For a long time it was widely accepted that GPCRs exist and function as a monomer. This paradigm has begun to shift such that, currently, the majority of the scientific literature favors the concept that GPCRs function as either dimers or higher-structure oligomers. Stimulation of such heteromers can lead to different signals than when each receptor type alone is activated. Bivalent drugs that can stimulate these heteromers might therefore have additional therapeutic value.

We have published on homodimerization of the D4R and heterodimerization of D4R and D2R. We are further concentrating on GPCR dimerization and are determining the interaction domain and the functional consequences of heteromerization. Most work to date has been in artificial heterologous systems and the in vivo relevance of dimerization of GPCRs is only beginning to be elucidated and may offer great potential for better, more selective therapeutic intervention.

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