Jak tyrosine kinases have a unique domain structure containing a kinase domain (JH1) adjacent to a catalytically inactive pseudokinase domain (JH2). JH2 is crucial for inhibition of basal Jak activity, but the mechanism of this regulation has remained elusive. We show that JH2 negatively regulated Jak2 in bacterial cells, indicating that regulation is an intrinsic property of Jak2. JH2 suppress...

Our understanding of the mechanisms of action of GH and its receptor, the GHR, has advanced significantly in the last decade and has provided some important surprises. It is now clear that the GH-GHR axis activates a number of inter-related signalling pathways, not all of which are dependent on the intracellular tyrosine kinase, JAK2 as originally postulated. JAK2-independent pathways, mediated...

The JAK2V617F mutation has been detected in most cases of Ph-negative myeloproliferative neoplasms (MPNs). The JAK2V617F protein is a constitutively activated tyrosine kinase that leads to transformation of hematopoietic progenitors. Previous studies have shown that several tyrosine residues within JAK2 are phosphorylated on growth factor or cytokine stimulation. However, the role of these tyro...

Sfingolipidy odgrywają rolę w licznych fizjologicznych oraz patofizjologicznych procesach, zachodzących w obrębie układu pokarmowego. W błonie komórkowej enterocytów sfingolipidy pełnią funkcję strukturalną, warunkują absorpcję niektórych substancji dostarczonych z pożywieniem, a także mogą pełnić rolę receptorów dla niektórych mikroorganizmów i syntetyzowanych przez nie toksyn. Bioaktywne lipi...

Jak2 (Janus kinase 2) initiates the signal transduction of many cytokine receptors. We discovered that Jak2 is SUMOylated on multiple lysine residues by SUMO2/3 (small ubiquitin-related modifier 2/3) chains. Analysis of Jak2 mutants revealed that Jak2 SUMOylation depends on the presence of an active catalytic site. We used the GH (growth hormone) receptor to study the physiological relevance of...

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) induces proliferation and sustains the viability of the mouse interleukin-3-dependent cell line BA/F3 expressing the hGM-CSF receptor. Analysis of the antiapoptosis activity of GM-CSF receptor betac mutants showed that box1 but not the C-terminal region containing tyrosine residues is essential for GM-CSF-dependent antiapoptotic a...

Recent studies have demonstrated that patients with myeloproliferative disorders (MPDs) frequently have acquired activating mutations in the JAK2 tyrosine kinase. A multikinase screen determined that lestaurtinib (formerly known as CEP-701) inhibits wild type JAK2 kinase activity with a concentration that inhibits response by 50% (IC(50)) of 1 nM in vitro. We hypothesized that lestaurtinib woul...