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CHAPTER 17 AN OVERVIEW OF CELL SIGNALING

SIGNAL TRANSDUCTION Blood cells and their marrow-based progenitors are exquisitely
responsive to their environment. A wide variety of cues are detected
PATHWAYS 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 the extracellular matrix by engaging integrins, and then respond
Kenneth Kaushansky to chemotactic gradients to enter inflammatory foci to contact and
engulf microorganisms on encountering bacterial products. Likewise,
platelets adhere to reactive endothelial surfaces or denuded subendo-
thelial cell matrix by engagement of extracellular adhesive proteins.
SUMMARY Adherent platelets can also recruit additional platelets and aggregate
with them through interactions with platelet integrins, secrete growth
Most external influences upon cells of any organ are mediated by biochemical factors that will recruit cells that mediate repair of vascular injury and
and molecular mechanisms that are triggered by interactions with membrane, then contract to strengthen the platelet plug by engagement of numer-
cytoplasmic, or nuclear receptors. Our understanding of the receptors and the ous granule substances. Even the anucleate erythrocyte responds to
intermediate molecules that couple them with cellular pathways that influ- mechanical deformation and hypoxemia with adenosine triphosphate
ence the proliferation, activation, differentiation, or survival of hematopoietic (ATP) release. Adrenergic receptors also play important roles in the
cells has expanded significantly. Proteins on the surface of blood cells that normal erythrocyte response to parasitic infection or in the pathologic
transmit vital information from the extracellular environment include single- red cell’s interactions with endothelial cell surfaces (e.g., patients with
pass, homodimeric, heterodimeric, and heterotrimeric transmembrane pro- hemoglobinopathies). Each of these events induces an intracellular sig-
nal that leads to further cellular reactivity toward the initiating stimu-
teins that do, or do not, contain intrinsic kinase activity, but either way signal lus, or that prepares the cell for subsequent functional events. Like the
by inducing the tyrosine phosphorylation of a multitude of cytoplasmic pro- functional activation of mature blood cells, the generation of blood cells
teins, seven transmembrane domain proteins that signal through G proteins, is under tight regulation, mediated by soluble hematopoietic growth
heterodimeric integrins that recruit large focal adhesions, and large families factors, cytokines, and components of the marrow microenvironment.
of heterodimeric proteins that induce serine and threonine phosphorylation. Here again, the erythropoietin (EPO) response to anemia is sensed by
This chapter describes the receptors that influence blood cell production and erythroid progenitor cell surface receptors; their coordinated reaction
function, the secondary mediators and the biochemical modifications they involves a myriad of signals that impact on the survival, growth, and
undergo to alert the cell to an external influence, the molecular mechanisms differentiation of both undifferentiated and lineage-committed cells.
that allow for the coordination of multiple signals impacting a cell simultane- Although anemia induces red cell production and inflammation leads
ously, and the processes upon which they impact. to the production and functional activation of leukocytes, many of the
intracellular signals that mediate these two responses overlap substan-
tially. This chapter illuminates a number of principles that mediate the
growth and functional responses of blood cells and their progenitors in
health and disease. A better understanding of how blood cells respond
to their environment can lead to improved strategies to intervene in
pathologic processes in which too many or too few blood cells are pro-
duced, or in which the functional activation of blood cells is insufficient
Acronyms and Abbreviations: AP2, adaptor protein-2; BCR, B-cell antigen or overly exuberant and leads to disease. Moreover, a thorough knowl-
receptor; BMP, bone morphogenic protein; CNTF, ciliary neurotrophic factor; CT-1, edge of how the signaling pathways that mediate growth and cell sur-
cardiotrophin-1; DD, death domain; DR, death receptor; EPO, erythropoietin; EPOR, vival are disrupted in the hematologic malignancies has begun to allow
erythropoietin receptor; ERK, extracellular response kinase; FADD, Fas-associated the rational intervention in such diseases.
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 TYPES OF RECEPTORS AND THEIR
cytokine receptor; IAP, inhibitors of apoptosis; IKK, I-κB kinase; IL, interleukin; IRS, MECHANISMS OF ACTIVATION
insulin receptor substrate; ITAM, immunoreceptor tyrosine-based activation motif;
ITIM, immunoreceptor tyrosine-based inhibitory motif; JAK, Janus family kinase; THE HEMATOPOIETIC CYTOKINE RECEPTOR
JNK, c-Jun N-terminal kinase; LIF, leukemia inhibitory factor; M-CSF, macrophage
colony-stimulating factor; MAPK, mitogen-activated protein kinase; NR, nuclear FAMILY
receptor; OSM, oncostatin M; PI3K phosphoinositol 3′-kinase; PIAS, protein inhibitor The Erythropoietin Receptor
of activated STATs; PIP, phosphoinositol phosphate; PKC, protein kinase C; PTP, protein The erythropoietin receptor (EPOR) was cloned in 1989, settling sev-
1
tyrosine phosphatase; RACK, receptor for activated C kinase; RTK, receptor tyrosine eral controversies and setting many important paradigms in receptor
kinase; SARA, SMAD anchor for receptor activation; SCID, severe combined immuno- biology. Like other hematopoietic cytokines of this class (granulocyte
deficiency; SH2, Src homology 2; SOCS, suppressors of cytokine signaling; STATs, sig- colony-stimulating factor [G-CSF], thrombopoietin [TPO], and growth
nal transducers and activators of transcription; SUMO, small ubiquitin-like modifier; hormone [GH]), EPO binds to a homodimeric receptor with picomo-
2,3
TGF, transforming growth factor; TM, transmembrane; TNF, tumor necrosis factor; lar affinity. Numerous studies in these and multiple other cell-signaling
4
TPO, thrombopoietin; TRADD, TNF receptor death domain; TRAF, TNF receptor-associ- systems demonstrate the importance of phosphorylation of vital cyto-
ated factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand. plasmic mediators in signal transduction, yet one initial conundrum
5–7
was that the cloned EPOR bears no kinase domain. Rather, subsequent
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