Flashcards in Immune Receptors And Signal Transduction Deck (78)
What do the extracellular domains of receptors recognize?
Soluble ligands or membrane structures of neighboring cells.
How does ligand binding affect a receptor?
It causes a conformational alteration of the receptor.
What is the result of clustering and conformational alterations of a receptor?
It results in changes in the cytosolic portion of the receptor that promotes interactions with other signaling molecules.
What are nuclear receptors?
Intracellular transcription factors that are activated by lipid soluble ligands (estrogen, progesterone, retinoic acid, etc.) that can cross the plasma membrane.
What initiates signal transduction?
The enzymatic phosphorylation of tyrosine, serine or thronine in the cytosolic portion of th ereceptor.
What enzymes are responsible for the phosphorylation of tyrosine, serine or threonine in cytosolic portions of receptors?
What is the function of phosphatases?
They remove the phosphate residues on receptors and modulate signaling.
These phosphatases usually play inhibitory roles in signal transduction.
What other protein modifications facilitate signaling events?
The covalent addition of ubiquitin molecules that either target proteins for degradation or drive signal transduction.
Covalent addition of lipids that promote plasma membrane localization of signaling molecules.
Acetylation and methylation of N-terminal tails of histones, which modulate gene expression, DNA replication and DNA recombination.
What are the three tyrosin kinase families of modular signaling proteins?
These molecules are composed on distinct domains each with a specific binding or catalytic function.
What are unique domains found on modular signaling proteins?
SH2 domains that bind phosphotyrosine-containing polypeptides.
SH3 domains that recognize proline-rich stretches in polypeptides.
PH domains that recognize PIP3 or other phosphatidylinositol derived lipids.
What is the function of tyrosine kinase families?
They are key players in the regulation of immune functions.
What do SH2 domains present, and where does the tyrosine kinase bind to?
SH2 domains present Syk. ZAP-70 tyrosine kinases bind phosphotyrosine motifs in the Ag receptor complex.
What do SH3 domains bind to?
Proline-rich stretches in certain proteins.
What do Pleckstrin homology (PH) domains recognize?
What does Btk tyrosine kinase recognize?
A lipid moiety on the inner leaflet of the plasma membrane termed phosphatidylinositol trisphosphate.
True or false: adaptor proteins lack catalytic activity.
They contain only protein-protein interaction domains.
What do adaptor proteins only contain?
Protein-protein interaction domains.
What are adaptor proteins?
They are molecular hubs that physically link different enzymes and promote the assembly of complexes of signaling molecules.
What domains may an adaptor protein contain?
A few SH2 and SH3 domains.
What amino acid do adaptor proteins contain?
They can contain proline-rich stretches that can bind other proteins that contain the SH3 domains.
They may also contain tyrosine residues that may serve as docking sites for other signaling proteins with SH2 domains.
What is LAT?
An integral membrane protein that functions as an adaptor.
What is GADS?
A cytosolic adaptor protein.
What are the VAV proteins?
Guanine nucleotide exchange factors that activate actin cytoskeletal rearragements and transcriptional alterations.
What do activating receptor contain?
Separate polypeptide chains for recognition and associated signaling poplyeptide chains that contain cytosolic ITAMs.
ITAMs = immunoreceptor tyrosine-based activating motifs.
Where are ITIMs located in inhibitory receptors?
They typically have ITIMS located on the cytosolic protion of the same chain that uses its extracellular domain for ligand recognition.
What is Fc-gamma-RIIB?
An inhibitory receptor found on B cells and myeloid cells.
What does Ag binding and clustering result in?
Activation of an associated Src family kinase.
Once Ag binding and clustering occurs, what type of change occurs?
A conformational change unfolds the cytoplasmic tail of receptor and exposes tyrosine residues of an ITAM motif.
What is the function of Src tyrosine kinase?
It phosphorylates available tyrosines in the ITAMS.
What domains are found in Syk tyrosine kinase?
SH2 domains that each bind to an ITAM phosphotyrosine.
What is the function of activated Syk kinase?
It phosphorylates adaptor proteins and enzymes that activate downstream signaling pathways of the immune receptor.
What is the number of ITAMs phosphorylated correlated with?
It is a cytosolic interpretation of Ag affinity to the TCR.
What does stronger or prolonged binding of Ag to the TCR result in?
Increased number of phosphorylated ITAMS.
How can Ag affinity of TCR influence the nature of the cellular response at different stages of differentiation and activation?
Weak TCR signals are required for positive selection of T cells in the thymus.
Strong TCR signals in the thymus result in negative selection of T cells and their death by apoptosis.
What increases cellular activation?
What are coreceptors?
A transmembrane signaling protein on a lymphocyte that can faciliatate Ag receptor activation.
What is a function of coreceptors?
They can increase ITAM phosphorylation and activation of the Ag receptor.
CD4 and CD8 are coreceptors on T helper and cytotoxic T cells, respectively.
What are the two coreceptors involved in sostimulation in activation of T cells?
How is signaling modulated by inhibitory receptors?
CTLA-4 is an inhibitor of T cell receptor.
CD22 and FC-gamma-RIIB are inhibitory receptors in B cells.
What does the TCR complex consist of?
The alpha-beta TCR non-covalently linked to the CD3 and zeta proteins.
What is the association of the TCR complex proteins mediated by?
Charged residues in their transmembrane regions.
What are the properties of CD4 coreceptors?
They have four extracellular Ig-like domains.
A hydrophobic transmembrane region.
A highly basic cytoplasmic tail 38 amino acids long.
What are the properties of CD8 alpha and CD8 beta?
A single extracellular Ig domain
A hydrophobic transmembrane region
A highly basic cytoplasmic tail that is about 25 amino acids long.
On Ag recognition, what to TCR complexes cluster with?
CD4 or CD8.
Once TCR complexes cluster with CD4 and CD8, what happens?
CD-4 associated Lck becoms active and phosphorylates ITAMs of CD3 and zeta chains.
After CD4-associated Lck becomes active and phosphorylates ITAMs of CD3 and zeta chains, what happens?
ZAP-70 binds to the phosphotyrosines of the zeta chains that become self-phosphorylated and activated.
What does an active ZAP-70 activate?
Various adaptor proteins such as LAT.
What do various adaptor proteins, such as LAT, do?
They become docking sites for PLC gamma 1 and exchange factors that activate Ras and MAP kinases.
What dos the ligation of the TCR with Ag and CD-28-CD80/86 result in?
Rapid activation of phosphoinositide-3 kinase.
What does an activated PI3K do?
It converts PIP2 into PIP3.
PDK1 then activats a downstream Akt kinase.
What is the function of an activated Akt?
It contributes to cell survival by inactivating pro-apoptotic proetins of the Ccl-2 family of apoprotic proteins.
What is the activation pathway of AP-1?
Lck -> ZAP-70 -> LAT - > Grb-2 -> SOS -> Ras-GTP-> ERK -> AP-1
What is the eventual effect of activated LAT binding to PLC-gamma-1?
A cellular response
What is the cell signaling pathway of PLC-gamma-1?
LAT -> PLC-gamma-1 -> PIP2, IP3 -> increase in Ca -> DAG -> PKC -> numerous cellular responses.
What is involved in activating the IL-2 gene?
Multiple signaling pathways that converge in Ag-stimulated T cells.
What does calcium-calmodulin activate?
The Ras and Rac pathways generate AP-1.
What is the function of activated NF-KB?
It is translocated to the nucleus.
AP-1 and NF-KB regulate gene expression.
What are the three major groups of MAP kinases?
P38 MAP kinasaes
JNK, c-Jun NH2 terminal kinases.
These MAP kinases are activatd by phosphorylation.
What is the ERK pathway activated by?
What are the p38 and JNK MAP kinases activated by?
Rac-GTP from the Rho family GTPases.
What is ELK?
A transcription factor that activates transcripton of transcriptional factor Fos.
What is involved in the canonical NF-KB pathway?
IKK phosphorlates IKB, which indues polyubiquitinylation.
Ubiquiti induces recognition of IKB-UUUU by the proteasome and causes successive proteolytic degradation.
NF-KB is release and translocated to the nucleus, where gene transcription is activated.
What is the alternative pathway of NF-KB activation engaged by?
A restricted set of cell-surface receptors including CD40 expressed on B cells.
This pathway culminates in the activation of IKK-alpha.
In the alternative pathway, what protein dimerizes with ReIB to translocate into the nucleus?
What occurs when there is peptide recognition at CD80/86, MHC II & TCR, and CD40 & CD40L?
T helper cell activation
What occurs when there is cognate peptide recognition in the absence of c0-stimulation?
Activation-induced cell death or anergy.
What is clonal anergy?
A term that describes T cell unresponsiveness at the cellular level.
What is the hyporesponsive state?
It is characterized by a reduced capacity to synthesize IL-2.
True or false: anergic cells proliferate in response to appropriate Ag stimulation.
False. Anergic T cells do not proliferate in response to appropriate Ag stimulation.
What can anergy be broken by?
What can anergy be induced by?
Substimulatory levels of Ags in the absence of:
A costimulatory signal provided by soluble cytokines.
Interactions between costimulatory receptors on T cells and counter-receptors on APCs.
What is the result of TCR and CD28 signaling pathways?
They result in the activation of several transcription factors.
What is the function of NFAT in the nucleus?
It cooperates with AP1 and NF-KB to induce gene exprssion of a productive immune response.
What occurs when TCR engagement occurs in the absence of co-stimulation?
Clacium mediated signals induce the activation of NFAT only.
What is the function of NFAT alone?
It elicits the expression of a distinct set of anergy-inducing genes.
What are the products of genes that are expressed by NFAT?
The products of these genes inhibit T-cell function at different levels and induce a status of T-cell unresponsiveness.
What are the major surface molecules of CD4 T cells and APCs involved in T cell activation?
CD4 (signal transduction)
TCR/Class II MHC (antigen recognition)
CD3 (signal transduction)
CD28/B7-1/B7-2 (signal transduction)