Our laboratory is interested in the molecular mechanisms governing cytokine receptor signal transduction in hematopoietic stem and progenitor cells, and understanding how deregulation in these mechanisms results in hematological malignancies and cancer.
Cytokines and their receptors play critical roles in a vast number of physiological functions such as the formation of mature blood cells, the function of the immune system, stem cell maintenance, and metabolism. Binding of cytokines to cytokine receptors triggers conformational changes in receptors dimerization/oligomerization and results in the activation of cytosolic Janus tyrosine kinases (JAKs). Activated JAK kinases then phosphorylate tyrosine residues on the cytokine receptors, providing docking sites for SH2 domain-containing intracellular signaling proteins. These signaling proteins, including the signal transducers and activators of transcription (STAT) proteins, are then activated and signal transduction cascades are initiated.
We use cell biology, molecular biology, bone marrow transplantation, and structural biology approaches to study the signaling of cytokines, including the erythropoietin (Epo), the thrombopoietin (Tpo), and the granulocyte colony-stimulating factor (G-CSF). Epo is the primary cytokines that regulate red blood cell production. Tpo regulates megakaryocyte and platelet development, and is important for hematopoietic stem cell self-renewal. G-CSF critically controls granulopoiesis and is a potent inducer of mobilization of hematopoietic stem cells out of the bone marrow. Clinically, all three cytokines are used widely for therapeutic applications.
Upon cytokine stimulation, homo-dimerization of the receptors for Epo, Tpo, and G-CSF activates the intracellular tyrosine kinase JAK2. This triggers downstream signaling transduction pathways and leads to the proliferation, differentiation, and survival of hematopoietic cells. Constitutive activation of of these signaling events leads to oncogenic transformation in mice. Constitutive activation of JAK2 also has been implicated in hematological malignancies such as myeloproliferative neoplasms and leukemia.
Our laboratory’s current focus is in two main areas: regulation of the sensitivity of cytokine receptor signaling through the transport of receptor/JAK complex to the plasma membrane and the down-regulation of this complex upon ligand stimulation, and regulation of JAK2 kinase activation by cytokine receptors or oncogenic mutations in normal vs. malignant hematopoiesis.
