Page 100 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 7 Signaling Transduction and Metabolomics 71

which results in the phosphorylation of other cytokine receptors present at the plasma membrane of antigen-presenting cells and binds
as well as other substrate proteins. Among these substrates, the to the integrin receptor LFA-1 to promote cell–cell adhesion.
signal transducer and activator of transcription (STAT) family of Ligand binding to the extracellular domain induces clustering of
transcription factors are pivotal to JAK-mediated cytokine signaling. integrins, allowing separation of the different subunits cytoplasmic
STATs are phosphorylated on Tyr residues by JAKs upon cytokine portions forming interactions with cytoskeleton proteins involved
binding to the receptor. Phospho-STATs homo- or hetero-dimerize, in actin polymerization (outside-in signaling). Signals arising from
and translocate to the nucleus to activate gene expression. STATs are the cellular interior, including phosphorylation, can also separate
also phosphorylated on a serine residue via MAPK, which serves to these cytoplasmic domains and can affect ligand binding (inside-out).
strengthen the intensity of the signal. As part of the cytokine signaling Ligand binding to integrin receptors also signals to protein tyrosine
attenuation, STATs induce genes encoding for suppressors of cytokine kinases such as the SFKs and focal adhesion kinase (Fak). This part
signaling proteins (SOCS), which bind to phospho-tyrosine residues of the signaling is not completely understood, but appears to involve
of the cytokine receptor and JAK through SH2-binding domains. a domain in the β-integrin tail (NPXY motif) that binds talin,
JAK inhibitors, based on their ability to block cytokine signaling, which in turn recruits paxillin that binds Fak, which, once activated,
are used in allergic and rheumatoid arthritis disease therapy. phosphorylates SFKs to mediate integrin response.

Multichain Immune Recognition Receptors Tumor Necrosis Factor Receptors and Signaling

This family of receptors include antigen receptors in B and T Tumor necrosis factor receptors (TNFRs) influence inflammation,
lymphocytes, activating receptors in natural killer (NK) cells, and innate immunity, lymphoid organization and T-cell responses. There
immunoglobulin E (IgE) and Fc receptors. This class of receptors are approximately 19 different ligands for TNFR that mediate cellular
contains different integral membrane subunits that bind the ligand responses through 29 TNFRs. TNFRs are a family of single-membrane-
at the cell surface and transduce the signal. Ligand binding induces spanning proteins that contain an extracellular TNF-binding region
oligomerization of receptor subunits that contain immunoreceptor and a cytoplasmic tail. As in the case of other cytokine receptors,
tyrosine-based activation motifs (ITAMs) within their cytoplasmic ligand binding causes oligomerization and the formation of a mature
domains. These domains become phosphorylated on tyrosine resi- receptor complex that is required to transduce the signal. TNFRs
dues upon receptor activation. These phosphotyrosines are involved fall into three classes: (1) death domain (DD) containing receptors
in activation of a series of protein tyrosine kinases containing SH2 (fatty acid synthase, TNFR1, and DR3), which activate the caspase
domains that include Src (Src family kinase [SFK]), Syk (Syk or cascade via the DD-initiating extrinsic apoptotic pathway; (2) decoy
ZAP-70), and Tec (Btk, Itk, Rlk), which mediate immune signal- receptors, which lack a cytoplasmic tail and therefore cannot transmit
ing through downstream pathways that include MAPK, calcium the signal, making these receptors ligand sequesters; and (3) TNFR-
signaling, and NF-κB, among others. In Tec kinases, additional associated factor (TRAF) receptors such as TNFR2, which lack the
downstream targets include enzymes such as phospholipase C γ DD-recruiting TRAF proteins. In general, TRAFs are associated with
(PLCγ). The precise mechanism of this activation is not completely either proapoptotic or survival pathways through activation of the
understood, and in some cases, such as T-cell receptors, a protein NF-κB family of transcription factors and MAPK signaling (Erk,
tyrosine phosphatase (-CD45, which counteracts the action of SFKs) JNK, and p38). TRAFs activate NF-κB through ubiquitin-mediated
is regulated upon ligand binding. degradation of their inhibitor IκBα, which retains NF-κB inactive in
The activities of some of these receptors are the basis of immu- the cytoplasm. This process is initiated by phosphorylation of IκBα
notherapy in cancer. For example, programmed death-1 (PD-1) by the IκBα kinase (IKK) complex, mainly by the IKK-β catalytic
mediates tumor-induced immunosuppression. Cancer cells express subunit, and requires a regulatory subunit (also known as NEMO).
the PD-1 ligand, which activates the PD-1 receptor present in tumor- Upstream of IKKs are other kinases including NF-κB-inducing kinase
infiltrated lymphocytes, suppressing the immune response. Blockade (NIK), which binds to TRAFs. Nuclear-activated NF-κB modulates
of PD-1 activation with monoclonal antibodies has been successful gene expression, which mediates TNF biologic responses.
in treating several human tumors such as melanoma. Mechanistically,
T cells are activated through the T-cell receptor upon binding of major
histocompatibility complex (MHC) plus peptides on an antigen- Toll-Like Receptors and Signaling
presenting cell (APC; in this case in the tumor cell), and binding
of APC CD80/86 to T cell CD28. Activation of the T-cell receptor Toll-like receptors (TLR) play essential roles in the innate immune
increases expression of PD-1 to suppress the immune/inflammatory response. Ten TLRs have been identified and can be grouped into
response. Cancer cells activate this pathway, upregulating the PD-1 two classes based on their extracellular domain: (1) TLRs with
ligand to promote survival and suppress the immune-mediated death leucine-rich repeats; and (2) TLRs with immunoglobulin domains.
of tumor cells. The ligands for TLRs are diverse and include the different constituent
components of the microorganism, such as lipopolysaccharides and
heat shock proteins (which bind to TLR2 and TLR4). Host defense
Integrin Signaling against microorganisms mainly relies on signals originating from the
TIR (Toll/IL-1) intracellular domain (a domain present in TLRs and
Integrin receptors are involved in cell adhesion, migration, survival, IL-1Rs). The TLR signaling pathway is similar to the one triggered
and growth. This signaling is central in hematopoietic cell function, by the IL-1R. Ligand binding induces TLR multimeric receptor com-
for example, at places of inflammation or infection, where integrins plexes, recruiting adaptor proteins such as MyD88, which contains
trigger a cascade by which leukocytes exit the vasculature. Interestingly, a TIR domain and a death domain, that in turn binds to the IL-1R-
these receptors signal bidirectionally through the plasma membrane associated kinase (IRAK). IRAK is activated by phosphorylation and
in pathways referred to as inside-out and outside-in signaling. Integrins then associates with TRAF6, leading to activation of mainly two
are a class of receptors that comprise heterodimeric type I transmem- different pathways, JNK and NF-κB to activate the innate immune
brane proteins consisting of α and β subunits. These subunits contain response, including release of inflammatory cytokines.
a large extracellular domain, a single transmembrane domain, and
a short cytoplasmic tail. There are 18 α and 8 β subunits that are
associated and form 24 different integrins with different affinities for Wnt Signaling
ligands. Most of the ligands are ECM proteins containing one of the
two motifs: arginine–glycine–aspartate (RGD) or leucine–aspartate– Wnt proteins are lipid-modified, secreted proteins of approximately
valine (LDV). Examples of integrin ligands are ICAM-1, which is 400 amino acids that bind to Wnt cell surface transmembrane