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Receptor tyrosine kinase signaling
Extracellular signals activate receptor-triggered signal transduction pathways. At the same time receptor tyrosine kinases (RTKs) initiate a cascade of events of ‘negative signaling’ that decrease the amplitude of positive signals and modulate the level of growth factor-induced stimulation. Hence, the same receptor simultaneously induces positive and negative signals.
RTKs are activated by ligand binding, autophosphorylated and ubiquitinated, i.e. the small molecule ubiquitin is attachted to lysine residues at various sites. Following internalization the ubiquitinated receptor is shuttled to the endosomal/lysosomal pathway which finally terminates signaling. Negative receptor signaling involves the coordinated action of ubiquitin ligases like c-Cbl, adaptor proteins like Grb2, negative feedback molecules like Sprouty, cytoplasmatic kinases and phosphoinositol metabolites.
We are particularly interested in the function and trafficking of fibroblast growth factor receptors. FGFRs are abundant in the nervous system and display several key roles in brain development and disease.
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Peripheral axonal regeneration
Over the recent years the cellular basis for insufficient or incorrect axonal regeneration and consequent lack of functional recovery has been unraveled in various laboratories. Neurotrophic factors such as FGFs or the neurotrophins are crucially involved in stimulating neurite outgrowth after nerve injury.
Ongoing research in many laboratories worldwide focusses on three different aspects. 1) The molecular mechanisms of neuronal survival in response to lesion, 2) the modifications of neuronal gene and protein expression patterns required for axonal regeneration and 3) the changes in the axonal environment particularly within the distal part of the lesioned nerve.
Our laboratory is interested in the elucidation of intrinsic mechanisms of neurite outgrowth and axon regeneration activated by stimulation of receptor tyrosine kinases, in particular by FGFR1.
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