Understanding the interplay between JAK2 and SOCS3 in blood diseases
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
| (Primary) | Cancer and Haematology | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Cancer and Haematology | .(JavaScript must be enabled to view this email address) |
Details of project
Maintenance of the blood system is largely controlled by the secretion of small glycoprotein messengers called cytokines. Cytokine exposure initiates an intracellular signalling cascade that is driven by activation of a family of receptor-bound tyrosine kinases known as JAKs (Janus Kinases). Under physiological conditions, JAK activation and signalling is tightly regulated, in particular by the SOCS (Suppressors of Cytokine Signalling) proteins. However, in certain disease situations, mutant JAK overcomes its regulation by SOCS, leading to haematological malignancies. One example of this is the myeloproliferative disorders.
The National Cancer Institute (U.S) describes the myeloproliferative disorders as “a group of slow growing blood-cancers” in which there is over-proliferation of one or more haematological cell types. 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 signaling 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 signaling 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.
Project references
- Babon JJ, Sabo JK, Zhang JG, Nicola NA, Norton RS. The SOCS box encodes a hierarchy of affinities for Cullin5: implications for ubiquitin ligase formation and cytokine signalling suppression. J Mol Biol. 2009 Mar 20;387(1):162-74. PMID: 19385048
- Boyle K, Zhang JG, Nicholson SE, Trounson E, Babon JJ, McManus EJ, Nicola NA, Robb L. Deletion of the SOCS box of suppressor of cytokine signaling 3 (SOCS3) in embryonic stem cells reveals SOCS box-dependent regulation of JAK but not STAT phosphorylation. Cell Signal. 2009 Mar;21(3):394-404. Epub 2008 Nov 12. PMID: 19056487
- Babon JJ, Sabo JK, Soetopo A, Yao S, Bailey MF, Zhang JG, Nicola NA, Norton RS. The SOCS box domain of SOCS3: structure and interaction with the elonginBC-cullin5 ubiquitin ligase. J Mol Biol. 2008 Sep 12;381(4):928-40. Epub 2008 Jun 20. PMID: 18590740
- Babon JJ, McManus EJ, Yao S, DeSouza DP, Mielke LA, Sprigg NS, Willson TA, Hilton DJ, Nicola NA, Baca M, Nicholson SE, Norton RS. The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability. Mol Cell. 2006 Apr 21;22(2):205-16. PMID: 16630890
- Babon JJ, Yao S, DeSouza DP, Harrison CF, Fabri LJ, Liepinsh E, Scrofani SD, Baca M, Norton RS. Secondary structure assignment of mouse SOCS3 by NMR defines the domain boundaries and identifies an unstructured insertion in the SH2 domain. FEBS J. 2005 Dec;272(23):6120-30. PMID: 16302975
Research interests
- Structural biology
- Enzyme kinetics
- Cytokine signalling
- Leukaemia
Research theme
Cancer
Scientific discipline
- Molecular Biology
- Structural Biology