Chapter 9 Cell Signaling Events - Elsevier

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Chapter 9Cell Signaling Events

© 2020 Elsevier Inc. All rights reserved. 2

Figure 9–1. Fibroblast growth factor (FGF) signal transduction pathways. Activated FGF receptors (FGFRs; red rectangles)

stimulate the phospholipase Cγ (PLCγ) pathway (blue highlight), the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B (PKB)

pathway (yellow highlight), and the FRS2-RAS-mitogen-activated protein kinase (MAPK) pathway (green highlight). The activated MAPKs

(extracellular signal-regulated kinases (ERKs), p38, or c-Jun N-terminal kinases (JNKs)) are translocated to the nucleus where they

phosphorylate (P) transcription factors, thereby regulating target genes. (Modified from Dailey L, et al. Cytokine Growth Factor Rev

2005;16:233, by permission.)


Figure 9–2. Activation and feedback regulation of the MAPK pathway. The classical MAPK pathway is activated in human tumors by

upstream receptor tyrosine kinases (RTKs) or by mutations in RAS, BRAF, and MEK1. RTKs activate RAS by recruiting adaptor proteins

(e.g., GRB-2) and exchange factors (e.g., Sos). RAS activation promotes the formation of RAF dimers, which activate MEK-ERK cascade

through phosphorylation. ERK pathway activity is regulated by negative feedback at multiple levels, including the transcriptional activation

of DUSP proteins that negatively regulate the pathway. ERK also phosphorylates and thus regulates CRAF and MEK activity directly.

ERK, or its immediate substrate RSK, also phosphorylates Sos at several residues, inhibiting its activity and thus negatively regulating

RAS activity. (From Liu, et al., Acta Pharm Sin B 2018;8(4):552–562.)


Figure 9–3. PI3 kinase-AKT pathway mutations in cancer. Mutations in PI3 kinase (p85 and p110) have widespread effects through

activation of AKT to promote cell survival, proliferation, enhanced metabolism, and protein synthesis. The PI3 kinase pathway

collaborates with the oncogenic RAS and is negatively regulated by the tumor suppressor PTEN. Red stars indicate mutations in the key

pathway regulators. Abbreviations for protein in the pathway: BAD, Bcl-2-associated death promoter; Grb2, growth factor receptor-bound

protein 2; IRS1, insulin receptor substrate 1; MDM2, murine double minute 2; mTOR, mammalian target of rapamycin; PDK1, 3-

phosphoinositide-dependent protein kinase 1; PI3K, phosphoinositide-3 kinase; PIP2, phosphatidylinositol bisphosphate; PIP3,

phosphatidylinositol triphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome ten; RAPTOR, regulatory associated

protein of TOR; RICTOR, rapamycin-insensitive companion of mammalian target of rapamycin; TSC, tuberous sclerosis.

(From Baselga J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. The Oncologist 2011;16:12–19.)


Figure 9–4. JAK/STAT signaling pathway and associated disorders. Mutations in JAK and STAT protein dysregulation have been

associated with many human diseases with the most prominent being immunodeficiency and cancer. (By Baylee Porter, Maria Ortiz, and

Leszek Kotula, chapter authors’ figure.)


Figure 9–5. Relations between transforming growth factor-β (TGF-β) and TGF-β-like ligands and their type I and II receptors in

vertebrates. The Nodal ligand binds to the ActR-IIB-Alk4 heterodimer. The activated receptor transmits the Nodal signal via Smad2 and

3, which heterodimerize with Smad4 to activate target genes. The bone morphogenetic protein (BMP) signaling pathways are shown on

the right for comparison. (Modified from Shi Y, Massague J. Cell 2003;113:685, by permission.)


Figure 9–6. Schematic representation of bone morphogenetic protein (BMP) signal transduction pathways involved in

cardiogenic induction. The BMP signal can be transmitted via the TAK1 signaling pathway or via Smad proteins, in particular Smad1

and 4. The Smad1/4 heterodimer can bind the ATF-2 transcription factor activating it to transcribe BMP-responsive genes. The same can

be achieved by the alternate TAK1 pathway via the mitogen-activated protein kinases MKK3/6, which phosphorylate and activate the

stress-activated protein kinases p38 and c-Jun N-terminal kinase (JNK) to go on and activate ATF-2. (Modified from Monzen K, Nagai R,

Komuro I. Trends Cardiovasc Med 2002;12:263, by permission.)


Figure 9–7. Transforming growth factor-β (TGF-β) receptor signaling through Smad-independent pathways.

The TGF-β signal can be directed to different signaling pathways such as the TAK1/MEKK1 or Smad pathways. This will activate

presumably different gene programs through the activation of different transcriptional effectors such as c-Jun N-terminal kinase (JNK),

p38, mitogen-activated protein kinase (MAPK), or Smad. (Modified from Derynck R, Zhang YE. Nature 2003;425:577, by permission.)


Figure 9–8. Wnt signaling pathways are diverse. (A) The canonical Wnt/β-catenin signaling pathway is highly dependent on

availability of β-catenin. In the absence of Wnt ligand, β-catenin is marked for proteosomal degradation upon ubiquitination by β-TrCP.

Binding of Wnt ligand results in disruption of the destruction complex, preventing ubiquitination of β-catenin. β-Catenin can accumulate in

the cytosol for nuclear translocation, activating TCF/LEF transcription factors to promote gene transcription. (B) Noncanonical Wnt/Ca2 +

signaling relies on GPCR activation to release intracellular Ca2 + from the endoplasmic reticulum, which activates Ca2 +-dependent

enzymes such as calmodulin, calcineurin, and CaM kinases to facilitate Wnt/Ca2 + signaling response. (C) Wnt polarity signaling can

polarize cells to modulate cell motility especially during embryogenesis. (Modified from Miller JR. The Wnts. Genome Biol 2001;3:3001.1,

by permission.)


Figure 9–9. Wnt signaling in cancer. (A) Canonical Wnt pathway. In the absence of Wnt signaling, the β-catenin destruction complex

labels β-catenin for proteasomal degradation. In the presence of Wnt signaling, the destruction complex is inhibited, resulting in

stabilization and nuclear translocation of β-catenin, activating transcription of target genes. (B) The noncanonical planar cell polarity

(PCP) pathway activates signaling cascades resulting in cytoskeletal changes, as well as alterations in cell polarity, movement, and

survival. (C) Noncanonical Wnt/calcium pathway signaling activates intracellular calcium, which, in turn, reduces cell adhesion through

further signaling. (D) Noncanonical Wnt5/Fzd2 pathway. Wnt5 signals via the Fzd2 receptor and FYN activates STAT3 transcription

leading to epithelial-mesenchymal transition (EMT) in cancer cells. (From Sandsmark E, et al. Oncotarget 2017;8:9572–9586.)


Figure 9–10. SHH ligand can be cleaved into functionally distinct peptides. (A) SHH ligand undergoes intramolecular cleavage,

yielding two functionally distinct products: SHH-N, to which a cholesterol group is added and can translocate to the nucleus to block gene

transcription, and SHH-C, which diffuses freely into the cytosol. (B) Depending on its form, SHH can localize to different parts of the cell.

Uncleaved SHH ligand localizes intracellularly while palmitoylated SHH-N remains membrane bound. SHH-N without palmitoylation or

cholesterol groups remains soluble and can translocate to the nucleus to regulate gene transcription. (Modified from Goetz JA, et al.

Bioessays 2002;24:157, by permission.)


Figure 9–11. Hedgehog (HH) signaling impacts Gli transcription factor activity. (A) In the absence of HH ligand, Ptch exerts

inhibitory function on Smo, allowing formation of a complex comprised of Fused (Fu), suppressor of Fused (SuFu), and Costal 2 (Cos2).

The Fu-SuFu-Cos2 complex cleaves Gli transcription factors, producing a Gli fragment that contains no transcriptional activity. The

transcriptionally null Gli fragment translocates to the nucleus and presents a physical hindrance to other transcription factors, thus

preventing transcription of Gli target genes. (B) Binding of HH signal nullifies the inhibitory impact of Ptch on Smo, resulting in disruption

of the Fu-SuFu-Cos2 complex. Gli transcription factors thus remain uncleaved and can translocate to the nucleus while retaining their

transcription-activating features, promoting transcription of Gli target genes. (Modified from Bijisma MF, et al. Bioessays 2004;26:387, by

permission.)


Figure 9–12. SHH ligand is imperative for proper limb development. Digit formation is highly dependent on SHH ligand expression.

During embryonic development, distal areas with sustained SHH ligand expression will form longer digits, while areas with shorter and/or

reduced SHH ligand will form shorter or no digits. (From Tickle C, Nat Rev Mol Cell Biol 2006;7: 45–53.)


Figure 9–13. EndMT via Notch signaling during endocardial cushion and heart valve formation. (A) Anatomic overview of heart

valve development. The developing heart tube contains an outer layer of myocardium and an inner lining of endothelial cells separated by

an extracellular matrix referred to as the cardiac jelly. During heart valve formation, a subset of endothelial cells overlying the future valve

site are specified to delaminate, differentiate, and migrate into the cardiac jelly, a process referred to as endothelial-to-mesenchymal

transition (EndMT). (B) In the developing cardiac cushion, Notch signaling increases the level of transforming growth factor-β2 (TGF-β2),

which is known to increase the activity of the transcription factor Snail (or Slug). Snail activity may lead to downregulation of VE-cadherin,

an adhesion molecule needed for binding cells together. Downregulation of cell-cell adhesion within the endothelial cell layer may be the

first step in the delamination of endothelial cells and their migration into the cardiac jelly. Some evidence exists that Notch signaling may

activate Snail independent of TGF-β signaling (dashed line). Note that this signaling is between endocardial cells, that is, autocrine

signaling, and not between endocardial and myocardial cells. (From Armstrong EJ, Bischoff J. Circ Res 2004;95:459, by permission.)


Figure 9–14. A model for Delta-dependent Notch signaling to the nuclear transcription factor CSL. Delta at the surface of the

signaling cell binds S1-cleaved Notch at the surface of the responding cell. Ligand-dependent S2 cleavage of Notch generates an

activated membrane-bound form of Notch called Notch extracellular truncation (NEXT), which is further processed at the S3 and S4 sites.

This releases the Notch intracel lular domain (NICD), which translocates into the nucleus where it derepresses CSL by displacing the

corepressor coR. (From Schweisguth F. Curr Biol 2004;14: R129, by permission.)


Figure 9–15. Model of a typical steroid hormone receptor. The glucocorticoid steroid hormone receptor provides a model for steroid

hormone receptor structure. The structural features leading to function are: (1) Steroid: the steroid-binding domain in the C terminus, and

(2) DNA: the DNA-binding domain that binds the receptor to specific response elements in the promoters of steroid hormone-responsive

genes. Other functional domains include transcription activation subdomain, which recruits molecules of the transcriptional apparatus to

the responsive gene’s promoter; nuclear localization signal, which is used in translocating hormone-bound receptor to the nucleus; heat

shock protein binding site, which binds heat shock protein 90 (Hsp90) in the unbound state to prevent the unoccupied receptor from

binding DNA; and zinc fingers, which are protein structural motifs that intercalate into DNA-helical grooves to provide physically tight

binding of receptor to DNA. (From Devlin TM, ed. Textbook of Biochemistry With Clinical Correlations, 5th ed. New York: Wiley-Liss,

2002.)


Figure 9–16. Stepwise model of steroid hormone action. Step 1: Dissociation of free hormone from circulating transport protein. Step

2: Diffusion of free ligand into cytosol or nucleus. Step 3: Binding of ligand to unactivated cytoplasmic or nuclear receptor. Step 4:

Activation of cytosolic or nuclear hormone-receptor complex to activated, DNA-binding form. Step 5: Translocation of activated cytosolic

hormone-receptor complex into nucleus. Step 6: Binding of activated hormone-receptor complexes to specific response elements within

the DNA. Step 7: Synthesis of new proteins encoded by hormone-responsive genes. Step 8: Alteration in phenotype or metabolic activity

of target cell mediated by specifically induced proteins. (From Devlin TM, ed. Textbook of Biochemistry With Clinical Correlations, 5th ed.

New York: Wiley-Liss, 2002.)


Figure 9–17. GPCR signaling. Upon binding of a ligand or agonist, a conformational change in the GPCR protein releases the Gα- and

Gβγ-subunits, giving GEF function to the GPCR. GEF activity allows the GPCR protein to stimulate release of GDP molecules, allowing

for binding of GTP molecules in their place. Release of GDP allows for the Gα- and Gβγ-subunits to continue GPCR-mediated signaling

by activating several effector proteins such as adenylyl cyclase, which, in turn, increases cAMP levels. Increased cAMP activates protein

kinase A (PKA), which can phosphorylate several substrates such as other 7-transmembrane receptors and transcription factors.

(Modified from Pierce, et al. Nat Rev Mol Cell Biol 2002;3:639–650, by permission.)


Figure 9–18. Diversity of G-protein coupled receptor (GPCR ligands and subunits. A wide variety of ligands use GPCRs to activate

different signaling pathways in the cell. The α-subunit of G-proteins is divided into four subfamilies (Gαs, Gαi, Gαq, and Gα12), and a single

GPCR can couple to any of these interchangeably, all activating different downstream effectors. Alterations in GPCR signaling pathways

can result in cancer progression and metastasis. (From Dorsam, et al. Nat Rev Cancer 2007;7:79–94.)


Figure 9–19. Model for the agonists-induced JAK/STAT signal transduction pathway. Agonist binding to the respective receptors

triggers the tyrosine phosphorylation and activation of tyrosine kinase JAK2, which associates with the AT1 receptor and activates

downstream signaling components such as STATs. Activated STATs are heterodimerized and translocated into the nucleus, where they

activate transcription of target genes.


Figure 9–20. (A) CaM kinase activation. Ca2 + entry into the cell controlled by neurotransmitter (N.T.) or hormone (Horm.) receptor

activation increases the intracellular Ca2 + concentration. Ca2 + ions are bound by calmodulin (CaM), and the Ca2 +/calmodulin complex

activates kinases such as CamKI, -II, and -IV. Ca2 +/calmodulin can also translocate to the nucleus and activate a nuclear isoform of

CaMKII, CaMKIIδB, to phosphorylate and activate certain widely used transcription factors (e.g., ATF1). (B) Calcineurin activation. Ca2

+-dependent activation of calmodulin (as in Panel A) leads to activation of the phosphatase calcineurin. Activation of G-protein coupled

receptors causes formation of IP3 (1) that binds to and activates IP3 receptors (2) on the endoplasmic reticulum (ER). Calcineurin

dephosphorylates the IP3 receptor, facilitating release of Ca2 + stored in the ER into the cytosol (3), and subsequent activation of plasma

membrane-bound Ca2 + channels (4).


Figure 9–21. Cancer cells require specific characteristics to initiate the metastatic cascade. Malignant tissues are characterized by

their ability to adapt to a microenvironment that is designed to eliminate threats to the host. As such, cancer cells gain the ability to thrive

in their environment even when they are depleted of nutrients and attacked by the immune system and can even colonize distal tissues to

spread. (From Welch DR, Hurst DR. Cancer Res 2019, https://doi.org/10.1158/0008-5472.CAN-19-0458, based on Hallmarks of Cancer,

Hanahan and Weinberg, 2011 Cell 144 https://doi.org/10.1016/j.cell.2011.02.013.)


Figure 9–22. Pathogenesis of cancer cell metastasis. Patient mortality results in failure to contain tumor cells to the site of the primary

tumor, otherwise known as metastasis. The metastatic cascade involves four processes: cell motility and invasion, alteration of the tumor

microenvironment, cell plasticity, and colonization of proximal and distal tissues. (From Welch DR, Hurst DR. Cancer Res 2019,

https://doi.org/10.1158/0008-5472.CAN-19-0458.)


Figure 9–23. Cancer cell-signaling amplification is a multistep process that drives a positive feedback loop to support tumor

growth. Increased availability of extracellular ligand and cognate receptor causes receptor aggregation, hyperphosphorylation, and

activation. In turn, there is a surge in nuclear translocation of transcription factors to transcribe protumor genes, which can regulate their

own as well as other gene transcriptions, promoting neoplastic changes within the cells. Alternatively, amplification of certain signaling

cascades can also downregulate expression of specific tumor suppressors, either at the transcriptional level or by altering protein stability

after the protein has been translated. (By Baylee Porter and Leszek Kotula, chapter authors’ figure.)

Chapter 9 Cell Signaling Events - Elsevier

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