Chapter 15 Flashcards
Cell signaling
What are the five forms of signalling?
Endocrine
Paracrine
Autocrine
Synaptic
Contacts-dependent
What is endocrine signalling?
Long distance signaling by molecules secreted to the blood
What is paracrine signalling?
Local signaling to neighboring cells
What is autocrine signalling?
Signaling to the cell itself
What is synaptic signalling?
Signaling along nerves, involving an electrical pulse and neurotransmitters
What is contacts-dependent signalling?
Interaction between molecules on the surface of cells
What is the function of a coincidence detector?
A coincidence detector requires activation from two separate signaling events. This way the chance of coincidental activation is diminished.
It functions to incorporate two spatially separated signals into one signal
Define downstream and upstream
RNA
Downstream - towards 5’ end
Upstream - towards 3’ end
DNA
Downstream - towards the 3’ end of the coding strand
Upstream - towards the 5’ end of the coding strand
What is receptor desensitization/adaption?
Alteration of sensitivity following repeated stimulation, reducing a cell’s response to that level of stimulus
What is receptor down-regulation and up-regulation?
A cell decreases or increases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus
What is a receptor?
General term for a protein that binds a specific extracellular molecule (ligand) and initiates a response in the cell
What is receptor sequestration?
Change in the receptor conformation such that binding of the agonist does not activate the receptor
What is positive feedback?
The enhancing or amplification of an effect by its own influence on the process which gives rise to it
Generally promotes instability
Explain the mechanism of G-protein-coupled receptor (GPCR) activation?
When an external signaling molecule bind to a GPCR it causes a conformational change
The change triggers the interaction between the GPCR and a nearby G-protein
Alpha subunit dissociates from the receptor and the beta-gamma subunt
GTP is exchanged for GDP, which activated the alpha subunit
The G-protein alpha subunit then goes on to activate other molecules in the cell
Explain the mechanism of G-protein-coupled receptor (GPCR) activation?
When an external signaling molecule bind to a GPCR it causes a conformational change
The change triggers the interaction between the GPCR and a nearby G-protein
Alpha subunit dissociates from the receptor and the beta-gamma subunt
GTP is exchanged for GDP, which activated the alpha subunit
The G-protein alpha subunit and beta-gamme subunit can then relay messages and interact with other membrane proteins.
What is a G-protein?
Specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP)
G-proteins that associate with GPCRs are heterotrimeric - have three different subunits.
Active - bound GTP
Inactive - bound GDP
Identify cAMP
(Ring structure around phosphor atom)
What is Guanine nucleotide exchange factor (GEF)?
a) Protein that binds to a GTP-binding protein and activates it by stimulating release of tightly bound GDP, thereby allowing it to bind GTP
What is an interaction domain?
Compact protein module that binds to a particular structural motif in another protein (or lipid) molecule with which the signaling protein interacts
What is a kinase cascade?
A signal relay chain involving multiple protein kinases, each of which is activated by phosphorylation and then phosphorylates the next protein kinase in the sequence
What is a second messenger?
Small molecule that is formed in the cytosol, or released into it, in response to an extracellular signal and that helps to relay the signal to the interior of the cell
What defines an endrocrine cell?
Specialized animal cell that secretes a hormone into the blood
What is a protein kinase?
Enzyme that transfers the terminal phosphate group of ATP to a specific amino acid of a target protein
What is a neurotransmitter?
Small signal molecule secreted by the presynaptic nerve cell at a chemical synapse to relay the signal to the postsynaptic cell
What is GTP-ase activating protein (GAP)
Protein that binds to a GTP-binding protein and inactivates it by stimulating its GTPase activity so that its bond GTP is hydrolyzed to GDP
What is a scaffold protein?
Protein that organizes groups of interacting intracellular signaling proteins into signaling complexes
What is an adaptor?
Short, chemically synthesized, single-stranded or double-stranded oligonucleotide that can be ligated to the ends of other DNA or RNA molecules
What is a GTP-binding protein?
Proteins that bind GTP
What defines a hormone?
Hormones are the body’s chemical messengers, signalling molecules, and are part of the endocrine system
What is an ion-channel-coupled receptor (ICCR)?
Integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma
What is a local mediator?
A substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitised lymphocyte
What is a monomeric GTPase?
Have a molecular weight of about 21 kilodaltons and generally serve as molecular switches for a variety of cellular signaling events
What is phosphorylation?
A biochemical process that involves the addition of phosphate to an organic compound
What is the primary cilium?
Also known as Immotile cilia
A single primary cilia can be find nearly all mammalian cells
“Antennae”
Coordinate a large number of cellular signaling pathways, sometimes coupled with ciliary motility or to cell division and differentiation
What is a protein phosphatase?
A phosphatase is an enzyme that removes a phosphate group from a protein
What is a Serine/Threonine kinase?
Kinase enzyme that phosphorylates the OH group of serine or threonine (which have similar sidechains)
What is a Tyrosine kinase?
Kinase enzyme that can transfer a phosphate group from ATP to a protein in a cell.
It functions as an “on” or “off” switch in many cellular functions
The phosphate group is attached to the amino acid Tyrosine on the protein
What is a kinase?
A kinase is an enzyme that attaches a phosphate group to a protein
How can a signalling pathway be bistable?
By having a strong positive feedback mechanism a pathway may remain ”on” even after the stimuli has ended
What separates extra- and intracellular receptors?
Signal molecules that targets internal receptors need to cross the plasma membrane and have to be small and hydrophobic.
How can different cells respond in different ways to exactly the same signaling molecule even when they have identical receptors?
Cells with identical receptors can respond differently to the same signal molecule because of differences in the internal machinery. Cell with identical signaling pathways can respond differently to a stimuli if the final effectors are different.
How do “slow” and “rapid” signalling differ?
Fast takes < sec to min and involves intracellular signaling pathways that alters protein function
Slow takes min to hours and involves the making of mRNA and altered protein syntesis
Describe three ways in which a gradual increase in an extracellular signal can be sharpened by the target cell to produce an abrupt or nearly all-or-none response
- If more than one effector molecule is required to activate a given target molecule. At low concentration the target proteins will be inactive. As effector concentration increases the amount of targets with enough effectors bound will sharply rise. The more effectors required, the sharper the rise in response.
- If an effector activates one enzyme and simultaniously inhibits another enzyme with the reverse reaction. This is a common strategy in metabolic signaling, i.e. insulin signaling.
- If an effector triggers a positive feedback loop, contributing to its own further activation. For example, the product of an enzyme activates more of the same enzyme creating a self-accelerating response.
Name the binding target of PH domain
Phosphorylated inositol phospholipids
Name the binding target of the PTB domain
Phosphorylated tyrosines
Name the binding target of the SH2 domain
Phosphorylated tyrosines
Name the binding target of the SH3 domain
Proline-rich sequences
What is adenyl cyclase?
Enzyme with regulatory roles
All classes of adenylyl cyclases catalyse the conversion of ATP to cAMP and pyrophosphate. Requires Ma ions
What is arrestin (Arr)?
Proteins important for regulating signal transduction at G protein-coupled receptors
(suppressing activated receptors)
What is Ca2+/calmodulin-dependent kinase (CaM-kinase)?
Protein kinase whose activity is regulated by the binding of Ca2+-activated calmodulin, and which indirectly mediates the effects of Ca2+ by phosphorylation of other proteins.
Involved in phosphorylation of TFs
What is Calmodulin?
Calcium modulated protein.
Ubiquitous calcium-binding protein whose interactions with other proteins are governed by changes in intracellular Ca2+ concentration
What is a Cone photoreceptor?
Type of photoreceptor cells in he retina
Responsible for color vision and functions best in bright light
What is a CRE-binding (CREB) protein?
Tt binds to DNA sequences called cAMP response elements (CRE) thereby increasing or decreasing the transcription of the genes
What is Cyclic AMP (cAMP)?
3’,5’-cyclic adenosine monophosphate
- messenger. Forms when adenyl cyclase is activated (by alpha subunit of G protein). It then actives specific proteins.
Used for intracellular signal transduction
What is Cyclic-AMP-dependent protein kinases (PKA)?
Enzymes whose activity is dependent on cellular levels of cAMP
Regulates glycogen, sugar and lipid metabolim etc.
What is cAMP phosphodiesterase?
Converts cAMP into AMP by breaking the phosphodiester bond in turn reducing the cAMP levels
cAMP to adenosine 5’-monophosphate (5’-AMP)
What is Diacylglycerol (DAG)?
- messenger signalling lipid
Product of hydrolysis by enzyme PLC
What is G_q?
G-protein subunit which activates PLC
What is ínhibitory G protein (Gi)?
Family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses
Describe the Inositol phospholipid signaling pathway
Activated when a signal molecule binds to the receptor of a G-protein
Alpha subunit activates PLC -> PIP2 -> DAG + IP3
DAG remains in the phospholipid membrane. Binds PKC
IP3 moves into the cytoplasm, binds to IP3 gated Ca2+ release channels on membrane of ER to release Ca2+ which binds PKC
PKC phosphorylates and amplifies protein signals
What is an olfactory receptor?
Expressed in the cell membranes of olfactory receptor neurons and are responsible for the detection of odorants
What is phospholipase C-β (PLCβ)?
Enzyme bound to the cytoplasmic surface of the plasma membrane that converts membrane PI(4,5)P2 to diacylglycerol and IP3
What is protein kinase C (PKC)?
A Ca2+-dependent protein kinase that is activated by diacylglycerol
What is the regulator of G-protein signalling (RGS)?
Protein that is an α-subunit-specific GTPase-activating protein (GAP).
What is Rhodopsin?
m) Light-sensitive GPCR in rod photoreceptor cells of the retina
Rod photoreceptor (Rod)?
Cells in the retina of the eye that can function in less intense light than cone cells
Found concentrated at the outer edges of the retina and are used in peripheral vision
What is Ryanodine receptor?
Ca2+-release channel in the ER membrane that is activated by Ca2+ binding in the absence of IP3
What is stimulatory G-protein (G_s)?
G protein that activates adenylyl cyclase and thereby increases cyclic AMP concentration
What is trimeric GTP-binding protein (G-protein)?
Protein composed of three subunits, one of which is activated by the binding of GTP
What is Inositol 1,4,5-triphosphate (IP3)?
Second messenger that is released from a phospholipid in the plasma membrane and diffuses to the ER, where it opens Ca2+-release channels
How is the G-protein returned to its inactive state?
A GAP activates the GTPase activity of the G-protein, hydrolyzing the GTP to GDP
How is adenyl cyclase inactivated?
Inactivating the G-protein inactivates the adenylyl cyclase
How is cAMP inactivated?
cAMP is degraded by a phosphodiesterase
How is PKA inhibited?
R-subunits of PKA are activated by cAMP degradation, inhibiting PKA
How are phosphorylases inactivated?
Phosphorylates proteins are dephosphorylated by phosphatases
What is Ephrins?
The largest class of cell-surface-bound extracellular signal proteins
What defines the Transforming growth factor-β (TGFβ) superfamily?
Large family of structurally related, secreted, dimeric proteins that act as hormones and local mediators to control a wide range of biological functions in all animals
What is the Receptor tyrosine kinase (RTK)?
Cell-surface receptor that when activated by ligand binding adds phosphates from ATP to tyrosine side chains in its own cytoplasmic domain
What is Ras?
The founding member of a superfamily of monomeric GTPases that help to relay signals from cell-surface receptors to the nucleus
What is the Rho family?
A group of monomeric GTPases that regulate both the actin and microtubule cytoskeletons
What is the Focal adhesion kinase (FAK)?
Cytoplasmic tyrosine kinase present at cell-matrix junctions in association with the cytoplasmic tails of integrins
What is the Phosphoinositide 3-kinase (PI 3-kinase)?
A kinase that is involved in intracellular signaling pathways activated by cell-surface receptors and that phosphorylates inositol phospholipids at the 3 position of the inositol ring
What is an enzyme coupled receptor?
Cell-surface receptor in which the cytoplasmic domain either has enzymatic activity itself or is associated with an intracellular enzyme
What is the Tyrosine-kinase-associated receptor?
Cell-surface receptor that activates a tyrosine kinase that is noncovalently bound to the receptor
What is the MAP kinase module?
A three-component signaling module used in various signaling pathways in eukaryotic cells
What is the JAK-STAT signaling pathway?
One of several intracellular signaling pathways that leads from cell-surface receptors to the nucleus, it is distinguished by providing one of the more direct routes
What is the Pleckstrin homology (PH) domain?
Protein domain found in intracellular signaling proteins by which they bind to inositol phospholipids phosphorylated by PI 3-kinase
What is the SH2 domain?
A protein domain that is homologous to a region in Src, is present in many proteins, and binds to a short amino acid sequence containing a phosphotyrosine
What is TOR or mTOR?
A crucial signaling protein in the PI-3-kinase-Akt signaling pathway, so named because it is the target of rapamycin
What is Akt?
Serine/threonine-specific protein kinase that plays a key role in multiple cellular processes
What is Cdc42?
Controls the polarity of calmodulin, and the calcium regulatory process of bud emergence
What is a cytokine receptor?
Cell-surface glycoproteins that bind specifically to cytokines and transduce their signals. These receptors enable cells to communicate with the extracellular environment by responding to signals generated in the vicinity or in other parts of the organism
What is the Focal adhesion kinase (FAK)?
Involved in cellular adhesion and spreading processes (how cells move around)
What is the Janus kinase (JAK)?
Family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway
What is the MAP kinase module?
A mitogen-activated protein kinase
Specific to the amino acids serine and threonine
MAPKs are involved in directing cellular responses to a diverse array of stimuli
What is the phosphoinositide?
Major membrane-bound signaling molecules that regulate intracellular organelle transport, cytoskeletal dynamics, the function of ion channels and transporters, as well as signal transduction mechanisms.
What is the phospholipase C-γ (PLCγ)?
Type of PLC which is membrane-associated enzymes that cleave phospholipids
What is Rac?
Subfamily of the Rho family of GTPases
Small signalling G-proteins
What is the Ras-GAP?
Complex between Ras and GAP
GAP: GTPase-accelerating proteins, truns the G-protein activity off
What is the Ras-GEF?
Complex between Ras and GEF
GEF: Guanine-nucleotide exchange factors, enhances the G-protein signalling
What is the Ras-MAP-kinase signaling pathway?
Ras can activate an enzymatic cascade of MAP kinases
Results in changes such as alterations of key proteins and changes in gene transcription
What is RHEB?
Ras homolog enriched in brain (RHEB) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals.
The protein is largely involved in the mTOR pathway and the regulation of the cell cycle
What is Rho?
Prokaryotic protein involved in the termination of transcription
Rho factor binds to the transcription terminator pause sit
What is the Smad family?
Comprise a family of structurally similar proteins that are the main signal transducers for receptors of the transforming growth factor beta (TGF-B) superfamily,
Critically important for regulating cell development and growt
What is the STAT proteins?
Signal transducer and activator of transcription
Intracellular transcription factors that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation.
What is RTKs?
Receptor Tyrosine Kinase
Activated by dimerizing
Enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an “on” or “off” switch in many cellular function
What is Notch?
Cell-surface receptor and latent gene regulatory protein (attached to the membrane as part of the covalent structure of a transmembrane protein)
When activated, the domain in the cytoplasm is cleaved off and enters the nucleus to regulate its target genes
Its ligands are cell-surface proteins such as Delta
What is the Wnt protein?
A family of secreted signal molecules that act as local mediators and morphogens during development; they were initially discovered as the products of the Wingless gene in flies and the Int1 gene in mice
Describe the Wnt/β-catenin pathway?
A signaling pathway activated by Wnt binding to both the Frizzled receptor and the LRP co-receptor
What is Hedgehog proteins?
A group of secreted signal molecules that act as local mediators and morphogens during development and whose effects are mediated through the cell-surface receptor Patched and its binding partner Smoothened
What is Cibitus Interruptus (C_i)?
Latent gene regulatory protein
A target of hedgehog signaling
Is inactive presence of Hedgehog and is released in its active form in its absence, where it is transported into the nucleus.
What is the NFκB proteins?
Latent gene regulatory proteins that are present in most cells in both animals and plants and are central to many stress, inflammatory, and innate immune responses
What defines steroid hormones?
Hydrophobic signaling molecule with a characteristic four-ringed structure derived from cholesterol
What is β-catenin?
Protein that in humans is encoded by the CTNNB1 gene
Dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcription
What is Circadian clock?
Biochemical oscillator that cycles with a stable phase and is synchronized with solar time
The primary circadian clock in mammals is located in the suprachiasmatic nucleus (or nuclei) (SCN), a pair of distinct groups of cells located in the hypothalamus
What is disheveled (Dsh)?
Family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors
Define Frizzled
Family of G protein-coupled receptor proteins that serves as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.
What is Interference Hedgehog (iHog)?
Protein shown in this study to bind and to mediate response to the active Hedgehog (Hh) protein signal
Essential for Hedgehog signalling
What is IκB?
Enzyme complex that is involved in propagating the cellular response to inflammation
The IκB kinase enzyme complex is part of the upstream NF-κB signal transduction cascade
What is LDL-receptor-related protein (LRP)?
A receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis.
What is NFκB proteins?
Protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli
What is the Nuclear receptor super family?
Class og TFs
Regulate diverse functions, such as homeostasis, reproduction, development and metabolism
Nuclear hormone receptors function as ligand-activated transcription factors, and thus provide a direct link between signaling molecules that control these processes and transcriptional responses.
Define Patched (PTCH)
Binding partner with Smoothened (SMO), When Patched is inhibited, SMO accumulates
Cell surface transmembrane protein (receptor) receptor that plays a role in the Hedgehog signaling pathway
Define Smoothened (SMO)
Binding partner with Patched.
A protein that in humans is encoded by the SMO gene.
Smoothened is a Class Frizzled (Class F) G protein-coupled receptor
Is a component of the hedgehog signaling pathway and is conserved from flies to humans
What is the Hedgehog Signalling Pathway?
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation
What is Delta?
Cell surface protein that mediates cell-cell interactions central to the specification of a variety of cell fates during embryonic and postembryonic development of Drosophila melanogaster
What are the two mutational routes to uncontrolled cell proliferation and invasiveness of cancer cells and what defines them?
1) to make a stimulatory gene (a proto-oncogene) hyperactive
Dominant -only one of the cell’s two genes needs to undergo change.
2) make an inhibitory gene (a tumor suppressor gene) inactive:
Recessive - both the cell’s gene copies must be inactivated
What does APC do?
Tumor supressor gene - its normal function is to inhibit β-catenin by keeping it in the cytosol (APC increases the affinity of the degradation complex)
Excess of β-catenin can enter the nucleus and promote transcription of key target genes for cell proliferation
What defines latent gene regulatory proteins?
Are prevented from entering the nucleus until the cell receives an appropriate signal
List the four ways by which cells keep gene regulatory proteins out of the nucleus and subsequently release them, in Notch/Delta, Wnt, Hedgehog and NFκB.
Notch: Attached to the membrane as part of a protein. When a valid signal is received, the regulatory protein is cleaved and enters the nucleus.
β-catenin: The latent gene regulatory protein is actively degraded in the cytosol. When a valid signal is received, the protein is stabilized against degradation, allowing it to enter the nucleus
Cubitus interruptus: The latent gene regulatory protein is anchored to a cytosolic structure and released in response to an appropriate signal.
NFκB: The latent gene regulatory protein is bound to a protein that holds it in an inactive form. Upon receipt of an appropriate signal, the inhibitory protein is modified so that the gene regulatory protein is released in an active form and transported into the nucleus.
What are the two brad classes of cancer ciritical genes?
Proto-once genes
Tumor suppressor genes
Mutations in these genes can drive cells toward cancer
Why are gain-off-function mutations are often dominant and why loss-of-function mutations are often recessive
Oncogenes act in a dominant manner because gain-of-function mutations in a single allele are sufficient to generate too much activity of e.g. growth factors that drives cells toward cancer. Tumor suppressor genes are recessive because loss-of-function mutations in both alleles are required before an effect is seen
What activates the Wnt/β-catenin signaling pathway?
Pathway is activated by binding of the Wnt ligand to the receptor Frizzled, β-catenin is released from the axin/APC complex and translocate to the nucleus where it acts as a transcription coactivator that activate Wnt target genes
