Signaling Processes and Figures Flashcards
Figure 15–1 A simple intracellular signaling pathway activated by an extracellular signal molecule.
The signal molecule usually binds to a receptor protein that is embedded in the plasma membrane of the target cell and activates one or more intracellular signaling pathways mediated by a series of signaling proteins. Finally, one or more of the intracellular signaling proteins alters the activity of effector proteins and thereby the behavior of the cell.
Figure 15–3 The binding of extracellular signal molecules to either cell-surface or intracellular receptors.
In most cases, the receptors are transmembrane proteins on the target cell surface. When these proteins bind an extracellular signal molecule (a ligand), they become activated and generate various intracellular signals that alter the behavior of the cell. In other cases, the receptor proteins are inside the target cell, and the signal molecule has to enter the cell to bind to them: this requires that the signal molecule be sufficiently small and hydrophobic to diffuse across the target cell’s plasma membrane
Figure 15–4 Four forms of intercellular signaling.
(A) Contact-dependent signaling requires cells to be in direct membrane–membrane contact.
(B) Paracrine signaling depends on signals that are released into the extracellular space and act locally on neighboring cells. (C) Synaptic signaling is performed by neurons that transmit signals electrically along their axons and release neurotransmitters at synapses, which are often located far away from the neuronal cell body. (D) Endocrine signaling depends on endocrine cells, which secrete hormones into the bloodstream for distribution throughout the body. Many of the same types of signaling molecules are used in paracrine, synaptic, and endocrine signaling; the crucial differences lie in the speed and selectivity with which the signals are delivered to their targets.
Cellular Response (Fig 15-6)
Certain types of signaled responses, such as increased cell growth and division, involve changes in gene expression and the synthesis of new proteins; they therefore occur slowly, often starting after an hour or more. Other responses—such as changes in cell movement, secretion, or metabolism—need not involve changes in gene transcription and therefore occur much more quickly, often starting in seconds or minutes; they may involve the rapid phosphorylation of effector proteins in the cytoplasm, for example. Synaptic responses mediated by changes in membrane potential can occur in milliseconds (not shown).
Structure of IP3
Structure of cGMP
Activates protein kinase G (PKG) and opens cation channels in rod cells
Structure of DAG
Structure of cAMP
Switch proteins
Structure of GPCRs
FIGURE 13-11 Operational model for ligand-induced activation of effector proteins associated with G protein– coupled receptors.
- Binding of hormone induces a conformational change in receptor
- Activated receptor binds to Gα subunit
- Binding induces conformational change in Gα; bound GDP dissociates and is replaced by GTP; Gα dissociates from Gβγ
- Hormone dissociates from receptor; Gα binds to effector, activating it
5.
functional expression assay
structure of adenylyl cyclase
▲ FIGURE 13-15 Hormone-induced activation and inhibition of adenylyl cyclase in adipose cells.
FIGURE 13-20 Localization of protein kinase A (PKA)
to the nuclear membrane in heart muscle.
This A kinase– associated protein mAKAP anchors both PKA and cAMP phosphodiesterase (PDE) to the nuclear membrane, maintaining them in a negative feedback loop that provides close local control of the cAMP level. Step 1 : The basal level of PDE activity in
the absence of hormone (resting state) keeps cAMP levels below those necessary for PKA activation. Step 2: Activation of
FIGURE 13-21 Operational model of muscarinic acetylcholine receptor in the heart muscle plasma membrane.
FIGURE 13-23 The light-triggered step in vision.
The light-absorbing pigment 11-cis-retinal is covalently bound to the amino group of a lysine residue in opsin, the protein portion of rhodopsin. Absorption of light causes rapid photoisomerization of the cis-retinal to the all-trans isomer, forming the unstable intermediate meta-rhodopsin II, or activated opsin, which activates Gt proteins. Within seconds all-trans-retinal dissociates from opsin and is converted by an enzyme back to the cis isomer, which then rebinds to another opsin molecule.
FIGURE 13-24 Operational model for rhodopsin-induced closing of
cation channels in rod cells.
In dark-adapted rod cells, a high level of cGMP keeps nucleotide-gated nonselective cation channels open. Light absorption generates activated opsin, O* (step 1 ), which binds inactive GDP-bound Gt protein and mediates replacement of GDP with GTP (step 2 ). The free Gt
Role of opsin phosphorylation in adaptation of rod cells to changes in ambient light levels.
Light-activated opsin (O*), but not dark-adapted rhodopsin, is a substrate for rhodopsin kinase. The extent of opsin phosphorylation is directly proportional to the amount of time each opsin molecule spends in the light- activated form and thus to the average ambient light level over the previous few minutes. The ability of O* to activate
Gt
Synthesis of DAG and IP3 from membrane-bound phosphatidylinositol (PI).
Each membrane- bound PI kinase places a phosphate (yellow circles) on a specific hydroxyl group on the inositol ring, producing the phosphoinositides PIP and PIP2. Cleavage of PIP2 by phospholipase C (PLC) yields the two important second messengers DAG and IP3.
IP3/DAG pathway and the elevation of cytosolic Ca2
This pathway can be triggered by ligand binding to certain G protein–coupled receptors and several other receptor types, leading to activation of phospholipase C. Cleavage of PIP2 by phospholipase C yields IP3 and DAG (step 1 ). After diffusing through the cytosol, IP3 interacts with and opens Ca2
Regulation of contractility of arterial smooth muscle by nitric oxide (NO) and cGMP.
Nitric oxide is synthesized in endothelial cells in response to acetylcholine and the subsequent elevation in cytosolic Ca2
Activation of the Tubby transcription factor following ligand binding to receptors coupled to Go or Gq.
In resting cells, Tubby is bound tightly to PIP2 in the plasma membrane. Receptor stimulation (not shown) leads to activation of phospholipase C, hydrolysis of PIP2, and release of Tubby into
Tubby
Transcriptional activation
domain
DNA binding domain
Cytosol the cytosol ( 1 ). Directed by two functional nuclear localization sequences (NLS) in its N-terminal domain, Tubby translocates into the nucleus ( 2 ) and activates transcription of target genes ( 3 ). It is not known whether IP3 remains bound to Tubby.
Activation of gene expression following ligand binding to Gs protein–coupled receptors.
Receptor stimulation ( 1 ) leads to activation of PKA ( 2 ). Catalytic subunits of PKA translocate to the nucleus ( 3 ) and there phosphorylate and activate the transcription factor CREB ( 4 ). Phosphorylated CREB associates with the co-activator CBP/P300 ( 5 ) to stimulate various target genes controlled by the CRE regulatory element. See the text for details.
GPCRs
Linked to a trimeric G protein that controls the activity of an effector protein (here adenylyl cyclase)
Activate cytosolic or nuclear transcription factors via several pathways (here one involving protein kinase A)
Schematic model of Ski-mediated down-regulation of the response to TGF
Ski binds to Smad4 in Smad3/Smad4 or Smad2/Smad4 (not shown) signaling complexes and may partially disrupt interactions between the Smad proteins. Ski also recruits a protein termed N-CoR that binds directly to mSin3A, which in turn interacts with histone deacetylase (HDAC), an enzyme that promotes histone deacetylation (Chapter 11). As a result, transcription activation induced by TGF
General structure and ligand-induced activation of receptor tyrosine kinases (RTKs) and cytokine receptors.
The cytosolic domain of RTKs contains a protein tyrosine kinase catalytic site, whereas the cytosolic domain of cytokine receptors associates with a separate JAK kinase (step 1 ). In both types of receptor, ligand binding causes a conformational change that promotes formation of a functional dimeric receptor, bringing together two intrinsic or associated

kinases, which then phosphorylate each other on a tyrosine residue in the activation lip (step 2 ). Phosphorylation causes
the lip to move out of the kinase catalytic site, thus allowing
ATP or a protein substrate to bind. The activated kinase then phosphorylates other tyrosine residues in the receptor’s cytosolic domain (step 3 ). The resulting phosphotyrosines function as docking sites for various signal-transduction proteins (see
Figure 14-6).
JAK-STAT signaling pathway.
Following ligand binding to a cytokine receptor and activation of an associated JAK kinase, JAK phosphorylates several tyrosine residues on the receptor’s cytosolic domain (see Figure 14-5, bottom). After an inactive monomeric STAT transcription factor binds to a phosphotyrosine in the receptor, it is phosphorylated by active JAK. Phosphorylated STATs spontaneously dissociate from the receptor and spontaneously dimerize. Because the STAT homodimer has two phosphotyrosine–SH2 domain interactions, whereas the receptor-STAT complex is stabilized by only one such interaction, phosphorylated STATs tend not to rebind to the receptor. The STAT dimer, which has two exposed nuclear-localization signals (NLS), moves into the nucleus, where it can bind to promoter sequences and activate transcription of target genes.
wo mechanisms for terminating signal transduction from the erythropoietin receptor (EpoR).
(a) SHP1, a protein tyrosine phosphatase, is present in an inactive form in unstimulated cells. Binding of an SH2 domain in SHP1 to a particular phosphotyrosine in the activated receptor unmasks its phosphatase catalytic site and positions it near the phosphorylated tyrosine in the lip region of JAK2. Removal of the phosphate from this tyrosine inactivates the JAK kinase.
(b) SOCS proteins, whose expression is induced in erythropoietin-stimulated erythroid cells, inhibit or permanently terminate signaling over longer time periods. Binding of SOCS to phosphotyrosine residues on the EpoR or JAK2 blocks binding of other signaling proteins (left). The SOCS box can also target proteins such as JAK2 for degradation by the ubiquitin- proteasome pathway (right). Similar mechanisms regulate signaling from other cytokine receptors.
Activation of Ras following ligand binding to receptor tyrosine kinases (RTKs).
The receptors for epidermal growth factor (EGF) and many other growth factors are RTKs. The cytosolic adapter protein GRB2 binds to a specific phosphotyrosine on an activated, ligand-bound receptor and to the cytosolic Sos protein, bringing it near its substrate, the inactive Ras
Kinase cascade that transmits signals downstream from activated Ras protein to MAP kinase
In unstimulated cells, most Ras is in the inactive form with bound GDP; binding of a ligand to its RTK or cytokine receptor leads to formation of the active Ras
Induction of gene transcription
by activated MAP kinase
In the cytosol, MAP kinase phosphorylates and activates the kinase p90RSK, which
then moves into the nucleus and phosphorylates the SRF transcription factor. After translocating into the nucleus, MAP kinase directly phosphorylates the transcription
factor TCF. Together, these phosphorylation events stimulate transcription of genes (e.g., c-fos) that contain an SRE sequence in their promoter. See the text for details.
