Most external influences on cells of any organ are mediated by biochemical and molecular mechanisms that are triggered by interactions with membrane, cytoplasmic, or nuclear receptors. Our understanding of the receptors and the intermediate molecules that couple them with cellular pathways that influence the proliferation, activation, differentiation, or survival of hematopoietic cells has expanded significantly. Proteins on the surface of blood cells that transmit vital information from the extracellular environment include (a) single-pass, homodimeric, heterodimeric, and heterotrimeric transmembrane proteins that do or do not contain intrinsic kinase activity but either way signal by inducing the tyrosine phosphorylation of a multitude of cytoplasmic proteins; (b) seven transmembrane domain proteins that signal through G proteins; (c) heterodimeric integrins that recruit large focal adhesions; (d) large families of heterodimeric proteins that induce serine and threonine phosphorylation; and (e) a number of incompletely understood external influences such as neural signals, bacterial products, and lipids. This chapter describes the receptors that influence blood cell production and function, the secondary mediators and the biochemical modifications they undergo to alert the cell to an external influence, the molecular mechanisms that allow for the coordination of multiple signals impacting a cell simultaneously, and the processes on which they impact.
Acronyms and Abbreviations
aPC, activated Protein C; AP2, adaptor protein-2; BCR, B-cell antigen receptor; BMP, bone morphogenic protein; CNTF, ciliary neurotrophic factor; CT-1, cardiotrophin-1; DD, death domain; DR, death receptor; EPCR, endothelial protein C receptor; EPO, erythropoietin; EPOR, erythropoietin receptor; ERK, extracellular response kinase; FADD, Fas-associated death domain; FAK, focal adhesion kinase; G-CSF, granulocyte colony-stimulating factor; Gab, Grb binding; GH, growth hormone; GM-CSF, granulocyte-macrophage colony-stimulating factor; GPCR, G-protein-coupled receptor; HCR, hematopoietic cytokine receptor; HSC, hematopoietic stem cell; IAP, inhibitors of apoptosis; IKK, I-κB kinase; IL, interleukin; IRS, insulin receptor substrate; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; ILK, integrin-linked kinase; JAK, Janus family kinase; JNK, c-Jun N-terminal kinase; LIF, leukemia inhibitory factor; M-CSF, macrophage colony-stimulating factor; MAMP, microbe associated molecular pattern molecules; MAPK, mitogen-activated protein kinase; NR, nuclear receptor; OSM, oncostatin M; PI3K phosphoinositol 3¢-kinase; PIAS, protein inhibitor of activated STATs; PIP, phosphoinositol phosphate; PKC, protein kinase C; PTP, protein tyrosine phosphatase; RACK, receptor for activated C kinase; RTK, receptor tyrosine kinase; SARA, SMAD anchor for receptor activation; SCID, severe combined immunodeficiency; SH2, Src homology 2; SOCS, suppressors of cytokine signaling; STATs, signal transducers and activators of transcription; SUMO, small ubiquitin-like modifier; TGF, transforming growth factor; TM, transmembrane; TNF, tumor necrosis factor; TPO, thrombopoietin; TRADD, TNF receptor death domain; TRAF, TNF receptor-associated factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TRIF, TIR-domain-containing adapter-inducing interferon-β.
AN OVERVIEW OF CELL SIGNALING
Blood cells and their marrow-based progenitors are exquisitely responsive to their environment. A wide variety of cues are detected by mature blood cells that impact significantly on their function. For example, leukocytes respond to noxious stimuli by chemokine-induced migration toward inflammatory stimuli, cross endothelial cell barriers and ...