Protein kinases are enzymes that mediate the attachment of phosphate groups (from ATP) to serine, threonine, and/or tyrosine residues [1,2]. Thus, although it is clear that pro-TGF- binds to the EGF receptor, it remains unclear whether juxtacrine signaling by pro-TGF- can occur in some cellcell interactions or whether it only appears to exist and localized shedding at cellcell contacts actually leads to signaling. In addition, AEA acts as a weak partial agonist at the TRPV1 vannilloid receptor-channel, and also has lower affinity interactions with other receptors and signaling molecules in the body and brain (Van Der Stelt and Di Marzo, 2004; Oz, 2006). Smad 2 activation is induced by growth differentiation factor 15 (GDF15), a TGF- family member induced by pressure overload310 and facilitates antihypertrophic signaling. This protein clustering results in formation of an SDS-stable, high-molecular weight DISC that is internalized and serves as the site of caspase-8 activation (Feig et al., 2007). Maintenance of (A) hematopoietic stem cell (HSC), and (B) epithelial stem cell (EpSC) niches. This latter, depolarization-induced synaptic depression is termed depolarization-induced suppression of excitation (DSE) or inhibition (DSI) depending on whether the net effect is to decrease glutamatergic excitatory or GABAergic inhibitory synaptic transmission. Signals can be propagated from cell to cell in this way. For example, it is clear that TACE is required for activation of the EGFR by TGF- in tumors, a finding that also calls into question the importance of juxtacrine signaling by membrane-anchored growth factor.463 TACE belongs to a large family of zinc-dependent ADAMs.464466 These proteins are also variably referred to as sheddases or convertases. Two arachidonoyl-containing fatty acids, arachidonoylethanolamide (AEA or anandamide) and 2-arachydonoyl glycerol (2-AG) are thought to produce the majority of eCB signaling. However recent studies have questioned this idea and indicated instead that although pro-TGF- can bind the EGF receptor, this interaction does not lead to receptor signaling in the absence of shedding. Unlike traditional synaptic transmission, in which neurotransmitter release from the presynaptic axon terminal leads to postsynaptic receptor activation, retrograde signaling involves postsynaptic release of a compound that then acts on presynaptic receptors. Notch receptor activation leads to the cleavage of the Notch intracellular domain (NICD), which is then translocated to the nucleus. Subsequent studies corroborated this assertion. (2000) have reported corneal endothelial cell proliferation in response to exogenous EGF. Gq/phospholipase C pathways cross talk with PI3K/Akt signaling axis in transducing pathological hypertrophy signals. Xiaoya Ma, Yatrik M. Shah, in Physiology of the Gastrointestinal Tract (Sixth Edition), 2018. Cross talk of YAP1/TAZ, Notch, BMP, and Hedgehog pathways.

Epithelial cells are maintained in their niche by juxtacrine contact (bars) between themselves and with their basement membrane (BM) and by paracrine signals between the EpSCs and capillaries. In this manner, clustering of membrane receptors can enhance both the quantity and the signaling capacity of ligated receptors. Pradeep Nair, Avi Ashkenazi, in Methods in Enzymology, 2014. A second Akt pathway leads to phosphorylation and suppression of glycogen synthase kinase (GSK3, see Figure 2-10), and disinhibition of hypertrophy signaling. Membrane-bound Fas ligand (FasL), tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), and TNF can be cleaved by metalloproteinases to form soluble cytokines. Here, in addition to providing a scaffold for a greater number of ligandreceptor interactions, membrane receptor clustering also enhances recruitment of the downstream signaling molecules TRAF2 and TRAF3 to the receptorligand complex (Vidalain et al., 2000). In the case of eCB CNS actions, localization of synthetic enzymes for 2-AG suggests a postsynaptic locus of synthesis, while CB1 receptors are localized almost exclusively on presynaptic neuronal elements (Katona et al., 2001; Kofalvi et al., 2005; Katona et al., 2006; Uchigashima et al., 2007). The mechanisms controlling eCB release are not yet fully understood, and it is still not clear how the hydrophobic eCBs cross what is thought to be a hydrophilic extracellular environment to produce actions on nearby cells. In some studies, including inhibition of shedding by CD9, stimulation by pro-TGF- was reported to be even more effective than that by soluble TGF-. Mechanical properties of the ECM such as porosity, stiffness, elasticity, tension and compression play key roles in cell behavior as well (Ingber, 2006; Engler et al., 2006; Guilak et al., 2009). The eventual outcome is an alteration in cellular activity, and changes in the program of genes expressed within the responding cells [1,2]. Short-term depression (STD) can be produced by activation of postsynaptic metabotropic glutamate or acetylcholine receptors, and by depolarization of postsynaptic membrane potential. Stimulation of Fas with agonistic antibodies or crosslinked sFasL triggers recruitment of acid sphingomyelinase (ASM) to the external leaflet of the plasma membrane (Grassm, Jekle, et al., 2001), as well as palmitoylation of the membrane-proximal Cys199 of Fas (Feig, Tchikov, Schtze, & Peter, 2007). The CB1 receptor is the main mediator of eCB actions in the brain, and is responsible for the majority of the intoxicating effects of natural and synthetic cannabinoid drugs (Pacher et al., 2006). By continuing you agree to the use of cookies. The role of signaling downstream of two prototypical growth factors, neuregulin, and TGF- are reviewed here in detail. The Wnt--catenin signaling pathway is antihypertrophic in the heart.290 Cardiomyocyte-specific deletion of -catenin mildly increases cardiac mass and the cardiomyocyte cross-sectional area and upregulates hypertrophy gene expression.291 In contrast, -catenin stabilization decreases cardiomyocyte area, upregulates the atrophy-related protein IGFBP5, and attenuates Ang II-induced hypertrophy.291 In this instance, the attenuated hypertrophy was associated with cardiomyopathic decompensation, suggesting that the Wnt pathway suppresses adaptive hypertrophy.

All three isoforms of neuregulin are cleaved by membrane-bound metalloproteinases, producing an activated fragment that is released and associates with EGF receptor (juxtacrine signaling) (see Figure 2-11). John F. Kuemmerle, Kirk M. McHugh, in Physiology of the Gastrointestinal Tract (Fifth Edition), 2012. Short amino acid sequences of cell adhesive ECM components also act as signals by binding to cell surface receptors called integrins (Hynes, 2002). They are present in the extracellular space as secreted or in membrane-bound forms; they can also be produced by genetic engineering in the laboratory, and used in various clinical therapies. Wilson et al. Endocannabinoid juxtacrine and paracrine signaling is widespread throughout the brain and body, representing one of the most prevalent lipid/fatty acid-based intercellular communication systems in mammals (Pacher et al., 2006). Accordingly, the soluble form was suggested to mediate autocrine and paracrine signaling, whereas the membrane precursor was suggested to stimulate EGF receptors located on neighboring cells, a mechanism termed juxtacrine signaling. -catenin therefore accumulates in the nucleus and complexes with a transcription factor TCF/LEF1 (T-cell-specific transcription factor/lymphoid enhancer binding factor 1) by displacing its binding protein Groucho, facilitating gene transcription. Neuregulin-mediated EGF receptor signaling is activated by neurohormonal stimuli via -arrestin-mediated transactivation of the -adrenergic receptors.297 Neuregulin is induced by pressure overload paralleling the development of concentric hypertrophy298 and its levels decline along with those of ErbB2 and ErbB4 receptors during transition to dilated cardiomyopathy.299 Ablation of neuregulin 1 or ErbB2 and ErbB4 receptors causes cardiac hypoplasia and loss of trabeculation.296 Neuregulin signaling via Erb receptors primarily regulates cardiomyocyte survival and not hypertrophy as cardiomyocyte-specific ablation of ErbB2 receptor causes spontaneous development of apoptotic cardiomyopathy,300,301 which is rescued by adenoviral transduction of the antiapoptotic protein BXL-xl. Neuregulin is produced in the heart primarily by the endothelial cells and therefore functions as a paracrine growth factor. The two major neurophysiological actions involving eCBs are short-term and long-term synaptic depression (reviewed in Chevaleyre and Castillo, 2003; Lovinger, 2008). In addition, identification of which eCB mediates the different forms of STD and LTD at different synapses is not nearly complete, although there is strong evidence for 2-AG mediation of DSI, STD and LTD at some synapses (Chevaleyre and Castillo, 2003; Kim and Alger, 2004; Makara et al., 2005; Uchigashima et al., 2007; Sheinin et al., 2008). However, there is some evidence for pools of pre-synthesized eCB and regulated release, particularly in neurons of the central nervous system (Ronesi et al., 2004; Edwards et al., 2006; Adermark and Lovinger, 2007b). Exosomes from cultured placental explants or plasma from pregnant women have FasL and TRAIL on their membrane, and induce apoptosis in Jurkat T cells via NF-B, CD3, and JAK3 downregulation (Sabapatha, Gercel-Taylor, & Taylor, 2006; Stenqvist, Nagaeva, Baranov, & Mincheva-Nilsson, 2013; Taylor, Akyol, & Gercel-Taylor, 2006). This process is termed shedding. paracrine autocrine endocrine differences moosmosis juxtacrine GLI, glioma-associated oncogene homolog; NICD, notch intracellular domain. Cardiac myocytes elaborate peptide growth factors in response to stress. We use cookies to help provide and enhance our service and tailor content and ads. From: Progress in Molecular Biology and Translational Science, 2016, David M. Lovinger, Rui M. Costa, in Handbook of Behavioral Neuroscience, 2010. Epidermal growth factor (EGF) potentially affects the cornea via autocrine, paracrine and juxtacrine signaling mechanisms (Nakamura et al., 2001). TGF- is transcriptionally induced during the transition from compensated hypertrophy to failure in the spontaneously hypertensive rat model of pathological hypertrophy. Endocrine signals circulate in the blood and bind to nuclear receptors. Cells that lack ASM exhibit less sensitivity to FasL, which can be restored through exogenous addition of ASM or C16-ceramide (Grassm, Jekle, et al., 2001). Figure 1.4. (1999a) reported the presence of mRNA for EGF in all three cell types that comprise the cornea while immunolocalization studies demonstrated higher levels of EGF protein in the superficial epithelial cells, the endothelial layer and a lower level in stromal cells. The signal transduction for the growth factors occurs primarily through transmembrane enzyme-linked receptors (Figure 7.1). ScienceDirect is a registered trademark of Elsevier B.V. ScienceDirect is a registered trademark of Elsevier B.V. Progress in Molecular Biology and Translational Science, Handbook of Basal Ganglia Structure and Function, Growth Factors and Neurotrophic Factors as Targets, Regulated Cell Death Part A: Apoptotic Mechanisms, Exosome-Mediated Communication in the Tumor Microenvironment, Diagnostic and Therapeutic Applications of Exosomes in Cancer, Schneider etal., 1998; Wajant etal., 2001, Sabapatha, Gercel-Taylor, & Taylor, 2006; Stenqvist, Nagaeva, Baranov, & Mincheva-Nilsson, 2013; Taylor, Akyol, & Gercel-Taylor, 2006, Taylor, Gercel-Taylor, Lyons, Stanson, & Whiteside, 2003, Physiology of the Gastrointestinal Tract (Sixth Edition), Regenerative Biology and Medicine (Second Edition), Ingber, 2006; Engler et al., 2006; Guilak et al., 2009, Growth Factors in the Gastrointestinal Tract, Physiology of the Gastrointestinal Tract (Fifth Edition), Stem Cell Biology and Tissue Engineering in Dental Sciences, Heart Failure: A Companion to Braunwald's Heart Disease (Second Edition). Secreted growth factors act on nearby cells through paracrine or contact juxtacrine signaling to mediate short-range cell-to-cell communications. One pathway involves activation of mTOR (mammalian target of rapamycin) and induction of protein synthesis. The cannabinoid part of the name is derived from the cannabis sativa plant and the drugs, marijuana and hashish among others, made from this plant. Blocking this adhesion inhibits hematopoiesis in long-term bone marrow cultures (Whetton and Graham, 1999). Whereas PI3K is activated by receptor-mediated tyrosine phosphorylation, PI3K binds to dissociated G, providing access to membrane phosphoinositides (see Figures 2-8 and 2-10).277 PI3K (p110) signaling is processed through Akt, which transduces both physiological and pathological cardiac growth (see Figure 2-10), depending upon the duration of activation.278 There is transient activation of p110 by exercise, but in pressure-overload/Gqmediated signaling, sustained activation of PI3K occurs with recruitment of additional signaling pathways in the phospholipase C and calcineurin/NFAT axis. Activation of these G-protein subtypes normally produces inhibition of adenylyl cyclase, inhibition of voltage-gated calcium channels, and activation of certain potassium channels. Currently, it appears that ADAM17 is the major protease involved in TGF-, AR, and HB-EGF shedding,467469 whereas ADAM10 is the major protease involved in shedding of EGF and BTC.436,468 Cleavage of HB-EGF by other metalloproteinases such as MMP-3 may also contribute to shedding.470, Shedding can be activated by a variety of stimuli, including phorbol esters, calcium ionophores, Ras activation, calmodulin antagonists, tyrosine phosphatases inhibitors, GTP-s, and EGFR autocrine signaling.374,471477 Emerging evidence indicates that the well-known phenomenon of EGFR transactivation by ligands of G-protein-coupled receptors (GPCRs) occurs by activation of ADAM activity, release of mature EGF-related peptide, and activation of the EGFR.478, A potentially important dividend realized by expanding our understanding of ADAM and MMP-induced shedding is the potential for modulating EGFR activation using metalloproteinase inhibitors. her2), which is effective against metastatic breast cancer, caused a high incidence of dilated cardiomyopathy.303, The transforming growth factor family is a large group of polypeptide growth factors divided into two groups: the TGF/activin subfamily and the bone morphogenic proteins (reviewed in Xiao304). Mei-Ju Su, Mansoor M. Amiji, in Diagnostic and Therapeutic Applications of Exosomes in Cancer, 2018. Smad 4 is the canonical effector of TGF-, and cardiomyocyte-specific ablation of Smad 4 causes cardiac hypertrophy with reexpression of fetal genes and the activation of the MEK1-ERK1/2 pathway.309 Thus Smad4 acts in opposition to TGF--induced MAPK activation. These are the fibroblast growth factor (FGF) family, the Hedgehog family, the Wnt family, and the TGF- superfamily, consisting of the TGF- family, the bone morphogenetic protein (BMP) family, the Nodal proteins, the Vg1 family, and several other proteins (Gilbert, 2010). Once released from postsynaptic cells, eCBs can persist at levels high enough to activate receptors for 10s of sec to several min (Robbe et al., 2001; Chevaleyre and Castillo, 2003; Kim and Alger, 2004; Ronesi et al., 2004; Makara et al., 2005; Szabo et al., 2006; Sheinin et al., 2008). At present the identification of molecular tools to examine transport and degradation are still at an early stage, and thus not much is known about which processes predominate at different synapses.

Forced cardiac expression of GDF15 attenuates pressure-overload hypertrophy, without affecting the fetal gene expression program310 and GDF15 ablation exaggerates hypertrophy, leading to rapid cardiomyopathic decompensation after pressure overload. Early studies gave rise to the conclusion that soluble mature TGF- or pro-TGF- can directly activate EGF receptors. In addition, overexpression of NICD leads to increased expression of YAP1/TAZ.

YAP1 binds to and negatively regulates the activity of GLI transcription factors, which, in turn, represses Hedgehog target genes. In LTD, the synaptic depression appears to outlast CB1 activation, and thus the receptor is thought to give rise to signaling within the presynaptic terminal that leads to a persistent decrease in neurotransmitter release probability (Chevaleyre et al., 2006; Lovinger, 2008). The simplest model of eCB production and release is that the compounds are made on-demand following calcium influx into cells and/or activation of metabotropic receptors (particularly receptors that couple to Gq-type G-proteins). Thus, receptor clustering serves as a feed-forward mechanism to amplify initial Fas stimulation.

J. Justin Hsuan, in Encyclopedia of Endocrine Diseases, 2004. Adding to the complexity is the high level of cell-type specificity of ADAM function. Thus, the predominant model of eCB signaling is that the compounds are synthesized and released from postsynaptic elements, traverse the synapses in a retrograde direction, and act on presynaptic CB1 receptors to decrease transmission.

Schematic drawing of molar crown development. Solid tissues, for example, behave much more normally if cultured in three-dimensional scaffolds. Several Notch pathway members are upregulated with YAP1 overexpression. The surface of the cornea is bathed in a tear film that contains EGF (Ohashi et al., 1989; van Setten et al., 1989) and thus can influence corneal epithelial cells that express both high and low affinity EGF receptors (Ohashi et al., 1989; Nakamura et al., 2001). The receptors for these drugs are the major targets of a group of lipid-derived signaling molecules known as the eCBs.

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There are many families of growth factors, including the Jagged/Delta/Serrate/Notch families, epidermal growth factor (EGF) family, fibroblast growth factors (FGFs) family, Hedgehog family, insulin-like growth factor family, IL-1 family, IL-6 family, IL-10/interferon family, IL-12 family, IL-17 family, platelet-derived growth factors (PDGFs) family, transforming growth factor beta (TGF-beta) superfamily, tumor necrosis factor (TNF) superfamily, vascular endothelial growth factor (VEGF) family, and Wnt family. Other intracellular signaling pathways, such as increased phosphorylation/activation of the multifunctional ERK kinase cascade can also result from CB1 activation (Wartmann et al., 1995; Davis et al., 2003). EGF was reported to inhibit epithelial cell differentiation and increase proliferation in a dose dependent fashion (Hongo et al., 1992; Wilson et al., 1999a; Imanishi et al., 2000). Juxtacrine signaling is a type of cell-to-cell signaling that is based on the interaction of a noncleaved ligand precursor and the EGFR. Of specific importance in these signal transduction pathways are transcription factors, which activate new genetic programs in the responding cells body [1,2]. The Notch pathway is a highly conserved pathway that is essential for cell fate determination and maintenance of ISCs.97 Notch signaling is a juxtacrine signaling pathway where the signal sending cells contains membrane-bound ligands (type I transmembrane proteins of the Delta/Serrate/Lag-2 (DSL) family) and activates receiving cell through binding to cell surface Notch receptors (Notch1-4). An autocrine signal is one that binds to receptors on the surface of the cell that produces it. Abhinav Diwan, Gerald W. DornII, in Heart Failure: A Companion to Braunwald's Heart Disease (Second Edition), 2011.

It has been learned that this is a complex, highly regulated process subject to therapeutic manipulation in diseases such as cancer in which EGF-related peptide signaling is often hyperactive. This class of receptors has a ligand-binding domain on the outer surface of the cell membrane, a trans-membrane domain that spans the lipid bilayer, and a cytoplasmic domain on the inner surface of the cell membrane containing protein kinase domains (tyrosine and/or serine/threonine kinases). Akt phosphorylates FoxO (O family of forkhead/winged-helix) transcription factors, which suppresses their transcriptional activity by facilitating interaction with 14-3-3 proteins, leading to export out of the nucleus and targeting for ubiquitin-proteasome degradation (see Figures 2-1 and 2-10). Because of their highly hydrophobic nature these compounds are not likely stored inside of vesicles, and there is no evidence for vesicular involvement in eCB release (Wilson and Nicoll, 2001). 5.3.

The significance of shedding as a key regulatory step in EGF-related peptide signaling was first highlighted by the observation that TACE gene-targeted mice develop a phenotype similar to TGF- and EGFR-null mice.250,285,462 TACE-null fibroblasts isolated from these mice had dramatically impaired ability to shed mature TGF- implying that cleavage of EGF-related peptides by TACE is critical for growth factor activity. Termination of the eCB synaptic signal is thought to involve enzymes that degrade AEA and 2-AG (Kim and Alger, 2004; Makara, 2005; Szabo et al., 2006) as well as cellular reuptake of the molecules (although the presence and identity of any transporter molecule that mediates this reuptake is controversial; see Lovinger, 2007, for discussion of this issue).

All EGF-related peptides are first synthesized as anchored transmembrane precursor proteins that are subsequently cleaved to release biologically active autocrine or paracrine peptide growth factor. The signaling molecules of the niche can be classified as paracrine, autocrine, juxtacrine, and endocrine. The binding of the growth factor to enzyme-linked receptors results in a conformational change in the structure of the receptor, leading to activation of the kinase function on the cytoplasmic domain through phosphorylation. David L. Stocum, in Regenerative Biology and Medicine (Second Edition), 2012. The activation and phosphorylation of the receptor result in the assembly and activation of a group of intracellular signaling proteins, leading to changes in the behavior of the target cells through the direct regulation of transcription factors, or through the regulation of mRNA stability or protein translation.

Inhibition of presynaptic voltage-gated calcium channels probably accounts for the presynaptic depression in STD. Interestingly, the mitogenic effect of EGF on corneal epithelial cells is dependent on the down-regulation of Pax6 (Li and Lu, 2005). NICD binds to the DNA-binding transcription factor CSL (CBF1/RBPjk/Su(h)/Lag1), leading to the increased transcriptional activity.98 Studies demonstrate that activation of Notch signaling in the intestinal epithelium increases the cell differentiation towards absorptive enterocytes, and inhibition leads to an increase in the secretory lineage (enteroendocrine, goblet, and Paneth cells).99 Notch inhibition leads to a significant decrease in active cycling ISCs.100 In addition, inhibition of Notch pathway has been considered as a promising target for cancer and increasingly reported in clinical trials in patients with solid tumor.101103 The initial success of Notch inhibition in decreasing cancer growth was dampened by the major side effects including gastrointestinal toxicity and diarrhea.104 Interestingly, Hippo signaling component YAP1 physically interacts with NICD and modulates the Notch signaling outputs.

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