Lecture 7: Immune Receptors and Signal Transduction Part I Flashcards
True or False:
Ligand-binding involves a conformational alteration of the receptor.
True
What does signaling require?
ligand-induced clustering of receptors, called cross-linking
What does clustering and conformational alterations result 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 do the extracellular domains of receptors recognize?
soluble ligands or membrane structures of neighboring cells
What does the phosphorylation of tyrosine, serine, or threonine in the cytosolic portion of the receptor do?
initiates the signal transduction
What do lipid kinases do?
phosphorylate lipid substrates
What do serine/threonine kinases do?
phsphorylate serine or threonine residues
What do tyrosine kinases do?
phosphorylate specific tyrosine residues
What do phosphatases do?
remove the phosphate residue and thus modulate signaling
What enzyme usually plays inhibitory roles in signal transduction?
phosphatases
What does the SH2 domain bind to?
binds phosphotyrosine
What does SH3 domain bind to?
binds proline-rich peptides
What does PH domain bind to?
binds inositol phospholipids (e.g., PIP3)
What are the 3 tyrosine kinase families?
> Src family (c-Src, Lyn, Ryn, and Lck)
> Syk family (Syk and ZAP-70)
> Tec family (Tec, Btk, and Itk)
What do SH2 domains (Src Homology 2) present?
Syk and ZAP-70 tyrosine kinases bind phosphotyrosine motifs in the Ag receptor complex.
How many amino acids are SH2 domains composed of?
100 amino acids
How many amino acids are SH3 domains composed of?
50 amino acids
What recognizes PIP3?
Btk tyrosine kinase recognizes a lipid moiety on the inner leaflet of the plasma membrane termed phosphatidylinositol trisphosphate (PIP3).
What do adaptor proteins lack?
catalytic activity
What are the only domains that adaptor proteins contain?
protein-protein interaction domains
What are adaptor proteins?
Molecular hubs that physically link different enzymes and promote the assembly of complexes of signaling molecules:
- LAT (Linker for the Activation of T cells)
- BLNK (B cell linker)
Can adaptor proteins contain a few SH2 and SH3 domains?
Yes
True or False:
Adaptor proteins often contain proline-rich stretches that can bind other proteins that contain SH3 domains.
True
What can adaptor proteins contain that may serve as docking sites for other signaling proteins with SH2 domains?
tyrosine residues
What is the mechanism of adaptor proteins in T cell activation?
1) LAT is phosphorylated and recurits PLCgamma and the GADS adaptor
2) SLP-76 (proline-rich stretch) associates with GADS via SH3 domain and recruits VAV after being tyrosine-phosphorylated.
3) the VAV proteins are guanine nucleotide exchange factors (GEFs) for GTPases that activate actin cytoskeletal rearrangemtns and transcriptional alterations.
What do activating immune receptors have?
separate polypeptide chains for recognition and associated signaling polypeptide chains that contain cytosolic ITAMs
What do inhibitory immune receptors have?
in the immune system typically have ITIMs on the cytosolic portion of the same chain that uses its extracellular domain for ligand recognition
What type of inhibitory receptor is found on B cells and myeloid cells?
Fc-gamma-RIIB
In TCR and BCR signaling, what causes activation of an associated Src family kinase?
Ag binding and clustering
What esposes the tyrosine residues of a ITAM motif in TCR and BCR signaling?
conformational change unfolds the cytoplasmic tail of receptor to expose the tyrosine residues of a ITAM motif
After activation of an associated Src family kinase due to Ag binding and clustering, what does the Src tyrosine kinase phosphrylate?
available tryosines in the ITAMs that was exposed do to the conformational change of the cytoplasmic tail of the receptor
How many SH2 domains does Syk tyrosine kinase have that bind to a ITAM phosphotyrosine?
has tandem SH2 domains
What do activated Syk kinases do?
phosphorylate adaptor proteins and enzymes that activate downstream signaling pathways of the immune receptor
What is the number of ITAMs phosphorylated a measure of?
cytosolic interpretation of Ag affinity to the TCR
What results in increasing numbers of phosphorylated ITAMs?
stronger or prolonged binding of Ag to the TCR
True or False:
Ag affinity of TCR can influence the nature of the cellular response at different stages of differentiation and activation.
True
What is required for positive selection of T cells in the thymus?
weak TCR signals
What kind of signal results in negative selection of T cells and their death by apoptosis in the thymus?
strong TCR signals
What is a coreceptor?
transmembrane signaling protein on a lymphocyte that can facilitate Ag receptor activation
What can the coreceptor with its signaling enzymes do?
increase ITAM phosphorylation and activation of the Ag receptor
What are CD4 and CD8 on T helper and cytotoxic T cells, respectively?
coreceptors
What is the coreceptor on B cells?
CR2/CD21
What is an example of costimulation in the activation of T cells?
CD28-CD80/86
In the modulation of signaling by inhibitory receptors, give an example of T cell receptor inhibition.
CTLA-4 (analog CD28)
What are inhibitory receptors in B cells?
CD22 and Fc-gamma-RIIB
