About us

Molecular mechanisms of cytokine signaling

The Molecular Immunology group investigates the mechanisms of cytokine signaling with a goal to implement this information to dissect disease mechanisms and evaluate therapeutic strategies through proof-of-principle experiments.

The JAK-STAT pathway mediates signaling for appr. 60 cytokines and hormones to regulate hematopoiesis, metabolism and orchestrate inflammatory and immune responses. Disturbances in JAK-STAT signaling pathways lead to various human diseases such as immune deficiencies, autoimmunity, allergy, metabolic diseases, hematological malignancies and cancer. The first JAK inhibitors are in clinical use for myeloproliferative neoplasms and autoimmune diseases, but there is unmet clinical need for more effective and specific drugs that would not affect normal signaling. Understanding of the mechanisms of JAK/STAT activation at molecular and atomic level will provide the molecular basis for designing intervention strategies and methodology for screening and development of therapeutic approaches. JAK kinases Deregulation of the JAK/STAT signaling pathway is directly involved in hematological malignancies and cancers and disease mutations are strongly concentrated in the pseudokinase (JH2) domain of JAKs. Our laboratory has conducted pioneering work on JH2 and initially demonstrated the regulatory function of this domain. More recently we have characterized the molecular mechanisms of JH2 and shown that JH2s bind ATP in a novel mode and identified the ATP binding pocket in JAK2 JH2 as a critical regulator for pathogenic activation. The JH2 regulation was found to be mediated by an autoinhibitory interaction between tyrosine kinase domains (JH1) and JH2. Importantly, the results provide molecular explanation for the majority of pathogenic mutations. Our current studies take a systematic structure/function approach to obtain understanding how JAKs are activated at receptor and the nature of regulatory interactions between different JH domains that may guide novel therapeutic approaches. SND1 Our other research interest relates to transcriptional and epigenetic regulation and focuses on SND1 protein, initially identified as transcriptional coactivator for STATs. SND1 is involved in transcriptional regulation and RNA biogenesis and the gene is highly overexpressed in cancer, especially prostate, colon and mammary cancers and B cell malignancies. The physiological function of SND1 is elusive and we have generated the first knockout mouse model where the function of SND1 is analysed using signaling, transcription, RNA/ncRNA expression and proteomic and interaction approaches. Our current interests are centered on in vivo cancer models (prostate, colon, leukemia, skin).