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70 Part I Molecular and Cellular Basis of Hematology

Membrane different cell cycle and antiapoptotic-related genes (see Fig. 7.2).
receptor Other MAPKs include the stress-activated kinases JNK and p38.
Constitutive MAPK in hematopoietic stem cells is known to induce
myeloproliferative disorders.
Sos
PI3K Phospholipase C
The Transforming Growth Factor-β Pathway
Ras
IP3 The TGFβ family of cytokines contains two subfamilies: the TGFβ/
Signaling PDK1 Raf Activin/Nodal and the bone morphogenetic protein (BMP)/growth
Molecules and differentiation factor (GDF)/Müllerian-inhibiting substance
Ca2+ (MIS) subfamilies. At the plasma membrane TGFβ ligands bind
MEK1
with high affinity to the ectodomain of type II receptors, which
Akt then recruit type I receptors. This forms a large ligand–receptor
ERK Calcineurin complex involving a ligand dimer and four receptor subunits. Upon
ligand binding, the type II receptor phosphorylates multiple serine
and threonine residues in the cytoplasmic GS-rich region of the
Transcription FoxO Elk1 NFAT type I receptor, leading to its activation. The phosphorylated TGFβ
Factors
type I receptor binds to and phosphorylates Smad2 and Smad3
Transcription transcription factors, which are critical mediators of TGFβ signaling
(Gene Expression) and function. Upon phosphorylation, Smad proteins translocate to
the nucleus to activate gene expression through binding to specific
Fig. 7.2 EXAMPLES OF SIGNALING/TRANSCRIPTIONAL PATH- DNA-binding sites. There are several mechanisms to terminate Smad
WAYS PROGRAMMING GENE EXPRESSION. Proteins involved in gene activation, which include proteasomal degradation and dephosphory-
expression are a common target of many signaling pathways, and receptors lation. TGFβ-1 has been shown to be associated with active centers
often stimulate multiple pathways that can regulate common and distinct of hematopoiesis and lymphopoiesis in the developing fetus.
transcription factors. In the examples shown here, production of PtdIns-
3,4,5-P3 by PI3K leads to the activation of the serine/threonine kinase Akt.
Akt phosphorylates and inactivate FoxO transcription factors. Ras is activated Signaling Through Receptors Associated With
by the guanine nucleotide exchange factor Sos. Ras activation initiates a Protein-Tyrosine Kinases
cascade of serine/threonine kinase activity: Ras activates Raf, Raf phosphory-
lates and activates Mek1, and Mek1 phosphorylates and activates Erk. Here, three different types of receptors and their signaling are
Phosphorylation of the transcription factor Elk1 by Erk activates gene expres- included: (1) cytokine receptors; (2) multichain immune recognition
sion. Increased intracellular calcium is also a common signaling event. Activa- receptors; and (3) integrin receptors.
tion of phospholipase C leads to hydrolysis of PtdIns-4,5-P2 and production
of IP3. IP3 binds to its receptor, leading to intracellular calcium release and
then extracellular calcium influx. Calcium activates the serine phosphatase Cytokine Receptors and Janus-Activated
calcineurin, which dephosphorylates NFAT proteins, allowing them to enter Kinase Signaling
the nucleus and stimulate transcription. FoxO, Forkhead transcription factors;
IP3, inositol triphosphate; NFAT, nuclear factor of activated T cells; PI3K, The cytokine receptor superfamily mediates many of the central
phosphatidylinositol 3-kinase; Sos, Son of Sevenless. specific responses in hematopoietic cells. Ligands for these receptors
include interleukins, thrombopoietin, erythropoietin, and so on.
Cytokine receptors possess a conserved extracellular region (cytokine
(Fig. 7.2). When phosphorylated by AKT, phospho-FoxOs are receptor homology domain [CDH]) and several structural modules,
sequestered and inactive in the cytoplasm through direct binding including extracellular immunoglobulin or fibronectin type III–like
to 14-3-3 proteins. Dephosphorylated FoxOs, on the other hand, domains, transmembrane domains, and intracellular homology
activate gene expression associated with stress resistance and cell regions. Based on the divergence of the CHD, cytokine receptors
growth arrest. Another major component downstream of Akt is mam- are classified into two classes: class I and class II receptors. Class I
malian target of rapamycin (mTOR, a kinase that belongs to the receptors contain two pairs of cysteines linked through a disulfide
PI3K-related protein kinase family), which is involved in metabolism, bond and a C-terminal WSXWS motif within the CHD. This class
growth, and proliferation. Akt phosphorylates TSC2, which forms a is further subdivided into three families: IL-2R, IL-3R, and IL-6R.
complex with TSC1, decreasing its GTPase-activating protein (GAP) All three receptor families share similar receptor chains. The class I
activity for the small GTPase Rheb; as a consequence, the increases cytokine receptors are formed by one chain containing two motifs
in GTP-Rheb activate mTORC1 (one of the mTOR complexes). (Box 1 and Box 2), which transduce signaling through binding to
Among the key downstream targets of mTOR are S6K and 4EBP1, Janus-activated kinase (JAK; see later discussion). Also included in
which control protein translation. mTOR can also be activated this class are the homomeric receptors that form homodimers upon
independently of RTKs through nutrients including branched chain ligand binding. Examples of these receptors include the erythro-
amino acids. Interestingly, mTORC1 inhibitors such as rapamycin poietin, thrombopoietin, prolactin, and growth hormone receptors.
are used as immunosuppressors in organ transplantation. Class II receptors also have two pairs of cysteines but lack the
WSXWS motif found in class I receptors. There are pools of 12 class
II receptor chains that are capable of forming a total of 10 receptor
MAPK/ERK Pathway complexes. This class is functionally divided into antiviral receptors
(three receptor complexes that bind interferons) and non-antiviral
Activated RTKs recruit docking proteins, such as Grb2 and SOS, receptors, which bind to several interleukins such as IL-10 and IL-20.
that allow binding of GTP to Ras to become active and trigger a The oligomeric structures of cytokine receptors are complex and
kinase signaling cascade. Ras activates RAF kinase that, in turn, cannot be generalized. Cytokine binding often induces oligomeriza-
triggers a series of MEKs, which finally activate MAPK or Erk tion, which activates protein tyrosine kinases in the JAK family
kinases. Erk phosphorylates many proteins involved in cell growth that are constitutively associated with the Box 1 and 2 motifs of
including ribosomal S6K, which is involved in protein translation, the cytokine receptor. Oligomerization brings JAKs in close enough
and AP-1 and c-myc transcription factors, which increase many proximity to transphosphorylate on Tyr residues. This activates JAK,