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Chapter 9 Cell Signaling Events

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Chapter 9 Cell Signaling Events Chapter 9 Cell Signaling Events © 2020 Elsevier Inc. All rights reserved. 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.) © 2020 Elsevier Inc. All rights reserved. 2 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.) © 2020 Elsevier Inc. All rights reserved. 3 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.) © 2020 Elsevier Inc. All rights reserved. 4 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.) © 2020 Elsevier Inc. All rights reserved. 5 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.) © 2020 Elsevier Inc. All rights reserved. 6 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.) © 2020 Elsevier Inc. All rights reserved. 7 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.) © 2020 Elsevier Inc. All rights reserved. 8 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.) © 2020 Elsevier Inc. All rights reserved. 9 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.) © 2020 Elsevier Inc. All rights reserved. 10 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.) © 2020 Elsevier Inc. All rights reserved. 11 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.) © 2020 Elsevier Inc. All rights reserved. 12 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.) © 2020 Elsevier Inc. All rights reserved. 13 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,
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