Membrane Trafficking & Signalling

At the core of the lab is the Protein Kinase D (PKD) family, which links signal transduction to membrane trafficking and the secretory pathway. We investigate how external cues control PKD activity and how the kinase engages its interactors and substrates to coordinate secretion, endolysosomal homeostasis and organelle function, from the molecular mechanism of kinase activation through to physiology and disease.

Mechanism and trafficking. Our recent work has uncovered new roles for PKD3 beyond the classical secretory pathway: PKD3 localises to late endosomes to maintain Rab7-dependent endolysosomal homeostasis, and supports lysosomal function and Wnt signalling to drive breast cancer stem cell formation. In parallel, we defined how PKD is autoinhibited and activated, providing a mechanistic framework for understanding PKD signalling.

PKD in cancer. PKD3 is upregulated in triple-negative breast cancer (TNBC) and promotes proliferation, invasion and metastasis. We study how PKD3 drives TNBC progression, through the secretion of invasion mediators, the maintenance of the cancer stem cell population, and its function at late endosomes and lysosomes, aiming to identify vulnerabilities that could be exploited therapeutically.

Disease-associated PKD1 mutations. De novo and inherited mutations in PRKD1 (the gene encoding Protein Kinase D 1) have been identified in patients with syndromic congenital heart disease and ectodermal dysplasia, and PRKD1 variants are also found in certain tumours. We use these disease-associated mutations to understand how altered PKD1 activity and localisation disrupt trafficking and signalling, and how this translates into disease phenotypes.

PKD in metabolism. Extending PKD biology into metabolic disease, we recently identified PKD as a key regulatory hub in β-cell ageing: PKD deficiency induces a senescence-like phenotype in β-cells and, unexpectedly, improves glucose and insulin tolerance under high-fat-diet conditions (Lieb et al., Molecular Metabolism 2026).

Small Rho-family GTPases such as RhoB organise the actin and microtubule cytoskeleton and thereby control cell shape, polarity and organelle positioning. Unlike RhoA and RhoC, RhoB also associates with endomembranes, where it regulates membrane trafficking, and its plasma-membrane versus endomembrane pools have been linked to opposing, oncogenic versus tumour-suppressive, functions. Building on our identification of the RhoGEF Solo as a positive regulator of endosomal RhoB, we dissect how Solo and GEF-H1 differentially control spatial RhoB signalling. Using genome editing to visualise endogenous RhoB in living cells, quantitative live imaging and optogenetic manipulation, we aim to resolve RhoB dynamics across epithelial and mesenchymal cell states, and how these relate to normal physiology and neoplastic transformation.

This work is pursued as a DFG-funded doctoral project (Prabin Bawali; joint with the group of Prof. Dr. Monilola Olayioye).

Synaptic plasticity, the activity-dependent strengthening (LTP) and weakening (LTD) of synapses, underlies learning and memory and is dysregulated in many neurological disorders. It depends both on the dynamic trafficking of AMPA-type glutamate receptors and on remodelling of the actin cytoskeleton at dendritic spines. The Ras-effector protein RIN1, highly expressed in forebrain glutamatergic neurons, has a dual role: it enhances Abl/Arg tyrosine-kinase signalling that remodels actin, and activates the small GTPase Rab5 to promote receptor endocytosis. Having shown that RIN1 destabilises hippocampal synapses, drives postsynaptic AMPA-receptor endocytosis and is required for spine plasticity during LTD, we now combine molecular manipulation of RIN1, biochemistry, subcellular localisation studies, live-cell imaging and electrophysiology to define how RIN1 coordinates AMPA-receptor trafficking and cytoskeletal remodelling during bidirectional synaptic plasticity.

This work is pursued as a DFG-funded doctoral project (Sara Suárez López; in collaboration with the group of Prof. Ingrid Ehrlich and Prof. Katalin Schlett).

As part of the DFG Research Training Group EpiSignal (GRK 3112), we investigate the crosstalk between cell signalling and the epigenome. DNA methyltransferases DNMT3A and DNMT3B are essential regulators of gene expression and chromatin organisation, and their dysregulation is implicated in cancer, yet how their activity is controlled remains poorly understood. This project studies how post-translational modifications (such as phosphorylation, ubiquitination and arginine methylation) regulate DNMT3A/B activity, localisation and stability in the context of TGFβ-induced epithelial-mesenchymal transition (EMT), stemness and breast cancer progression, integrating biochemical, proteomic and functional approaches.

This work is pursued as a doctoral project within the EpiSignal RTG (Anastasia Gaitanidou).