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248 Part IV: Molecular and Cellular Hematology Chapter 17: Signal Transduction Pathways 249

cells that express gp130. Furthermore, the same principles that allow engagement trigger apoptosis pathways, whereas recruitment of one of
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the rationale design of an EPO or GH antagonist can be used to engi- the seven TNF receptor-associated factor (TRAF) family members leads
neer IL-6 antagonists for treatment of pathologic states dependent on to activation of transcription factors such as nuclear factor-κB (NF-κB)
interactions with receptors that require gp130 for receptor signaling. 20 and kinases such as c-Jun N-terminal kinase (JNK) that lead to cell sur-
The Interleukin-2 Receptor Family The IL-2 family of receptors vival, proliferation, and activation of inflammation.
is also quite complex, in most cases sharing one, two, or three subun-
its with receptors for other cytokines of the same class (see Fig. 17–1).
IL-2Rβ is shared with the IL-15R, and IL-2Rγ (also termed γ [for com- THE RECEPTOR TYROSINE KINASES
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mon]) is shared with the IL-4, IL-7, IL-9, IL-15, and IL-21 receptors.
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Another feature of the IL-2R not yet discussed for the EPOR or IL-6R The receptor tyrosine kinases (RTKs) comprise another class of recep-
families is that of a devoted JAK. While JAK2 is employed by all the tors that contains members vital for hematopoiesis and mature blood
EPOR subfamily members along with some of the IL-6R subfamily cell function (see Fig. 17–1). The first hematopoietic member of this
members, and JAK1 and TYK2 are also shared amongst these latter family to be identified was the eukaryotic version of the v-fms oncogene,
receptors, the fourth and final JAK family member, JAK3, is engaged designated c-fms. Further study revealed that the protooncogene is the
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almost exclusively by γ (one study identified JAK3 activation by IL-8, sole receptor for macrophage colony-stimulating factor (M-CSF),
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implying use by the CXCR1 and/or CXCR2 receptors). In addition to and although somewhat distinct in possessing a split kinase domain,
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providing a more fundamental understanding of the principles of sig- was immediately grouped with other RTKs, such as the receptors for
nal transduction, careful investigation of the IL-2 family of receptors insulin, vascular endothelial cell growth factor and epidermal growth
also has afforded detailed insights into a number of clinically important factor, among several others. Subsequently, two additional hemato-
immunodeficiency states. The complexity of this family of receptors poietic receptor family members have been identified, c-Kit and Flt-3.
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was illustrated by the progressive investigation into the origins of severe These receptors were each cloned based on their homology to the viral
32,33
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combined immunodeficiency (SCID). As is discussed in Chap. 80, oncogene v-kit or c-fms, respectively. Like all other members of the
SCID is a severe loss of natural killer (NK) and T lymphocytes, and family, upon engagement of their cognate ligand the kinase domains of
has been traced to deficiencies of either γ or JAK3, a phenotype reca- homodimeric RTKs become activated, leading to the phosphorylation
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pitulated quite well (but not perfectly) by genetic elimination of the of receptor cytoplasmic domain tyrosine residues and other tethered
same molecules in mice. However, genetic elimination of IL-2 leads substrates. In an apparent example of convergent evolution, like mem-
to a phenotype quite different than SCID of humans or engineered bers of the hematopoietic cytokine receptor (HCR) family, RTKs were
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mice. Instead, of the multiple cytokines for which γ and JAK3 sup- also found to employ JAKs in their signaling pathways ; as a result,
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port signaling, only elimination of IL-7 or the IL-7R recapitulates the many of the same secondary signaling pathways are activated by both
phenotype, 25,26 a finding now consistent with the finding that IL-7 affects classes of receptors. But perhaps serving as an even more striking exam-
common lymphoid progenitors (Chap. 18), while other cytokines in the ple of convergent evolution, the tertiary structure of the index ligand
family affect more differentiated lymphoid cells. for a hematopoietic RTK, M-CSF, bears substantial homology to essen-
tially all the ligands of the HCR family, such as granulocyte-macrophage
colony-stimulating factor (GM-CSF). 35
THE TUMOR NECROSIS FACTOR RECEPTOR
SUPERFAMILY TRANSFORMING GROWTH FACTOR
At present the tumor necrosis factor (TNF) superfamily of receptors and
ligands comprises at least 30 receptors and 20 ligands, 27,28 and illustrates β FAMILY
several novel points in signal transduction pathways: trimeric binding The transforming growth factor (TGF) receptor family consists of seven
(see Fig. 17–1), receptor promiscuity, and decoy receptors. Although type I and five type II receptors that heterodimerize to form receptors
many TNF ligand family members (TNF-α, TNF-β, CD40L [CD154], for multiple TGF-β family members, including the TGF-β/activin/nodal
receptor activator of nuclear factor-κB ligand [RANKL; osteoprotegerin and bone morphogenic protein (BMP) subfamilies. The precise stoichi-
ligand (OPGL)], OX40L, etc.) can bind to several receptors, the ligands ometry of binding involves a ligand dimer, stabilized by disulfide and/
are, for the most part, subfamily specific. For example, TNF-α only or hydrophobic bonds, and two type I and two type II subunits (see Fig.
binds to the six TNF-α receptors and TNF-related apoptosis-inducing 17–1); the tertiary structure of the complex has been carefully investi-
ligand (TRAIL) binds to the five TRAIL receptors, although it can also gated. Both type I and type II receptors contain an N-terminal ligand
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bind to the receptor termed osteoprotegerin (OPG). Ligands in this fam- binding, transmembrane, and cytoplasmic ser/thr kinase domains; the
ily bind as trimers to homotrimeric receptors, leading to recruitment type I receptors additionally contain a Gly/Ser (GS)-rich domain. For
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of secondary signaling molecules to the cytoplasmic domain of the TGF-β subfamily members, the type II subunit bears a high-affinity lig-
receptors. In general, there are two classes of cytoplasmic domains in and binding site, which on TGF-β or activin engagement recruits type
these receptors, based on whether they contain the death domain (DD), I receptors, bringing the two cytoplasmic domains into close juxtapo-
a region capable of binding signaling mediators that initiate apoptosis sition, enabling the type II kinase to phosphorylate Ser residues on the
(Chap. 15). As such, receptors that do not contain a DD or other sig- type I receptor GS domain, thereby activating the type I kinase. Cell-
naling domain can function as “decoy receptors,” diverting ligand from surface-bound coreceptors also exist and aid in generating the signaling
initiating programmed cell death in the target cell. For example, among complex for TGF-β, but not activin or BMP ligands. For BMP family
the TNF-α receptors, TNFRI (death receptor [DR]2) contains a DD, and members, the type I receptor bears the high-affinity ligand binding
among the five TRAIL receptors, DR4 and DR5 contain DDs, whereas site, such that BMP initially binds to type I receptor, with the type II
TNFR2 and DcR1 and DcR2 and OPG act as decoy receptors for TNF subunit subsequently recruited to form the signaling complex. Once
and TRAIL, respectively. The biologic consequences of ligand binding the two receptor kinases are activated, they recruit and phosphorylate
to individual TNFR family members depend on the relative affinity of the SMAD (Sma- and Mad-related protein) adaptor proteins, allowing
their cytoplasmic domains for multiple adaptor proteins; TNF recep- their nuclear translocation and transcriptional activation. However,
tor death domain (TRADD) and Fas-associated death domain (FADD) SMAD-independent TGF-β signaling pathways also exist. 37

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