The Receptor-Interacting Protein Kinase family (RIPK) is a group of serine/threonine kinases, mainly involved in cellular stress responses. The members of the family share a homologous N-terminal kinase domain but significantly differ in their C-terminus, allowing their implication in distinct molecular pathways. Apart from being able to induce MAPK and NF-kB signalling pathways, RIPK4 has also been demonstrated to play an essential role during embryonic development of the epidermis. Loss-of-function mutations in RIPK4 have been identified in Bartsocas-Papas syndrome, a congenital disorder characterized by skin defects, pterygium and cleft palate. RIPK4 is also commonly mutated in cutaneous squamous cell carcinomas (cSCC) with UV signature. Recent studies of our lab have been focused on deciphering the role of RIPK4 in adult epidermal homeostasis. Tamoxifen-inducible keratinocyte-specific RIPK4 knockout mouse model (RIPK4^iEKO), developed by Tanghe et al. (in preparation), displays hyperproliferative epidermis with proinflammatory infiltration of CD8+ T cells and development of keratoacanthoma-like tumours, pointing towards a tumour suppressing role of RIPK4 in adult epidermis.

Our current research will focus on the following aspects of RIPK4 biology:

1) Decipher the molecular signaling axis involving RIPK4. Currently many questions are still open, such as how RIPK4 activity is regulated by autophosporylation, what are the downstream mediatiors of the RIPK4 signaling axis, what are the upstream regulators of RIPK4 activation. Our preliminary data point to a role of PKCs and IKK in the signaling cascade. This will be further investigated.

2) What is the involvement of the IL23-IL17A inflammatory response in the RIPK4-deficient adult murine epidermis phenotype (inflammation and tumor development)? Both cytokines are upregulated in RIPK4-deficient epidermis and are know to be able to drive inflammation and tumor development.

3) What is the effect of cancer-related RIPK4 mutations occuring in squamous cell cancer (SCC)? RIPK4 is often mutated in human SCC, however the effect of these mutations is not clear. This will be investigated using in-house developed cellular systems.