[Frontiers in Bioscience 12, 1463-1474, January 1, 2007] 1463 Src kinases in G-CSF Receptor Signaling Matthew Sampson 1 , Quan-Sheng Zhu 2 , and Seth J. Corey 2 1 Department of Pediatrics, Children’s Hospital of Philadelphia, 2 Division of Pediatrics and Department of Leukemia, The University of Texas, M. D.Anderson Cancer Center, Houston, Texas TABLE OF CONTENTS 1. Abstract 2. Introduction 3. The G-CSF Receptor 4. The Src family of protein tyrosine kinases 5. Interaction between G-CSF Receptor and protein tyrosine kinases 6. Tyrosine phosphorylation of the G-CSF Receptor 7. Intracellular signaling in myeloid cells 8. Role of Src kinases in G-CSF Receptor signaling 9. Implication of Src kinases in G-CSF Receptor signaling 10. Conclusions 11. Acknowledgements 12. References 1. ABSTRACT The Granulocyte Colony-Stimulating Factor (G- CSF) Receptor, a member of the hematopoietin cytokine receptor superfamily, functions as a homodimer and requires the recruitment of cytosolic protein tyrosine kinases (PTKs) to transduce its signal. At least two cytosolic PTKs are primarily involved: Jak2, a member of the Janus family, and Lyn, a member of the Src family. Through poorly understood mechanisms, these kinases functionally interact with the G-CSF Receptor. Jak2 primarily enlists members of the signal transducer and activator of transcription (STAT) family and Lyn phosphorylates a number of adaptor molecules, which link the G-CSF Receptor to phosphatidylinositol (PI) 3’-kinase and extracellular signal-regulated kinases (Erk) pathways. This review presents evidence that the Src kinases play a major role in the pathways of G-CSF-mediated proliferation, survival, and differentiation. Identification of Src-dependent pathways provides drug targets useful in the treatment of myeloid leukemias. 2. INTRODUCTION A small number of polypeptide growth factors, e.g. stem cell factor (SCF), Interleukin (IL)-3, IL-11, and granulocyte-macrophage colony stimulating factor (GM- CSF), drive hematopoietic stem cell expansion. A few more polypeptide growth factors, e.g. erythropoietin (Epo), G-CSF, monocyte-colony stimulating factor (M-CSF), thrombopoietin (Tpo), and IL-5, drive the differentiation of progenitors cells into lineage-restricted, differentiated myeloid blood cells (1). A few of these growth factors (e.g. SCF and M-CSF) have receptors that are tyrosine kinases. Almost all of the other hematopoietic growth factors have cognate receptors, which are members of the hematopoietin cytokine receptor (HCR) superfamily. The HCRs lack intrinsic enzymatic function and, instead, recruit cytosolic PTKs to transduce their signals (2). Common to both classes of hematopoietic growth factor receptors is rapid changes in cellular phosphotyrosine content. In turn, these tyrosine phosphorylated proteins lead to the activation of serine/threonine kinases. Both tyrosine and serine/threonine