Understanding the interplay between JAK2 and SOCS3 in myeloproliferative disease
Three closely related myeloproliferative disorders, Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) are characterised by over-proliferation of erythrocytes, thrombocytes and granulocytes which leads to thrombosis, increased risk of haemorrhage, stroke and heart attack, as well as a tendency to progress to leukaemia.
In 2005 these three disorders were shown to be associated with a single point mutation in JAK2, (V617F). This mutation results in constitutively active JAK2 and cytokine independent activation of downstream signalling pathways, resulting in over-proliferation of myeloid cells. Interestingly, JAK2V617F is susceptible to inhibition by SOCS3 and therefore SOCS3 potentially regulates both the onset and the severity of the disease.
Despite being intensively studied for more than a decade, the molecular details of JAK signalling, and its suppression by SOCS3, remains incomplete. We have the molecular tools required to dissect the SOCS/JAK interaction and aim to provide a full molecular description of the regulation of JAK signalling by SOCS. This includes dissecting the contributions of ubiquitination, proteolysis, and kinase inhibition to SOCS-mediated JAK suppression.
In addition, we aim to determine the structural details of the SOCS-JAK and SOCS-JAK-Receptor interactions in order to provide a scaffold for the future development of a new class of selective JAK kinase inhibitors. Finally, we aim to perform a complete biochemical and biophysical analysis of JAK itself, the interaction between its various domains, its substrate specificity and enzymatic efficiency.
All this information is crucial for understanding the progression and mitigation, both intrinsic and therapeutic, of myeloproliferative disorders. Given that aberrant JAK signalling is seen in a wide variety of human cancers it also highlights that an in depth understanding of the mechanism of signal transduction through the JAK/STAT pathway, will benefit knowledge of a wide range of human pathologies.
Figure legend: The two key suppressors of cytokine signalling (SOCS1 and SOCS3) associate with JAK whilst it is attached to a cytokine receptor and then inhibit its catalytic activity.