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Immunology
Signal Transduction (T Pierce)
35
Medical
Post-Graduate
01/25/2009

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Cards

Term
Components of receptor complex
Definition
  • antigen receptor heterodimer
  • invariant associated proteins that transmit signals
Term
components of TCR signaling complex
Definition
  • CD3 complex
  • TCR alpha/beta

All associated with motifs called ITAM's

Term
BCR signaling complex
Definition
Components of CD3 in B cell- Ig alpha and beta (associated with ITAM)
Term
Process of activating ITAM's
Definition
  1. ligand binds 
  2. phosphorylation of ITAM's by src family kinases
  3. phosphorylated ITAM's recruit other Tyr kinases and addaptor proteins
  4. this forms macromolecular signaling complex
Term
Cells that contain ITAM's
Definition
  • BCR
  • TCR
  • NK cells
  • macrophages
  • neutrophils
  • mast cells
  • basophils
Term
Functional advantage of receptor associated tyrosine kinases
Definition

allows flexibility of response due to major variations in quantity and quality of second messanger generation

Term

Methods to regulate formation of signaling macromolecular complexes

Definition
  • protein protein interactions
  • cytoskeletal interactions
  • segregation into lipid raft membrane microdomains
Term
Process of protein protein interaction
Definition

use SH2, SH3

  1. ligand binding clusters receptors, activating Tyr kinases leading to phosphorylation of receptor cytoplasmic domains
  2. adaptor proteins bind to phosphotyrosine via their S2 domains
  3. other signaling proteins bind to adaptor protein via Proline-rich sequences, becoming concentrated around activated receptor
Term
Protein protein interactions mediated by what within the signaling molecules?
Definition
specific domains
Term

Mechanism of phopshorylation of scaffolding prtoeins

Definition

phosphorylation of scaffolding protein leads to recruit signaling proteins that bind to it

Term
Structure of lipid rafts. Contents?
Definition
  • structure
    • enriched for saturaed lipids and cholesterol
    • can change in size and protein content
    • allow for proteins to migrate into lipid rafts when oligomerized by binding ligands
  • contents
    • GPI linked proteins
    • acylated proteins (ex: src family kinases)
Term

How does an immunological synapse form?

Definition
  • microclusters of TCR complexes form right after MHC-peptide binding
  • gradually coalesce into central aggregate
  • signal transduction initiated in microclusters within seconds of ligand recognition
Term
Co-Receptors of TCR
Definition

CD4

CD8

Term

Co-Receptors for BCR

Definition

CD21

CD19

Term

Process of TCR activation in co-receptors

Definition
  1. binding of ligand to receptor
  2. phosphorylation of ITAM by receptor associated kinases
  3. ZAP bind to phosphorylated ITAM chaim
  4. ZAP is phosphorylated and activated by Lck when co-receptor binds to MHC ligand
Term
Process of co-receptor activation of BCR
Definition
  1. CD21 binds to CD3 tagged antigens to allow for co-receptor to cluster with antigen receptors
  2. co-ligation of coreceptor allows receptor associated kinases of phosphorylated CD19
  3. phosphorylated CD19 bind src family and PI-3 kinases
  4. PI-3 kinase initiages signaling path to involve GEF protein (vav)
Term

Components of src gene/receptor

Definition

SH3 domain

SH2 domain

kinase domain (activating, inhibitory residues)

Term

Enzymes the regulates src family kinases

Definition
  • Csk phosphorylates inhibitory Tyr
  • CD45 dephosphorylates inhibitory Tyr
Term
How do src family tyrosine kinases know to phosphorylate ITAM's after antigen recognition?
Definition
  • recruitment of constitutively active kinases to antigen R by co-receptors
  • mobilization of antigen receptor to lipid raft domains after ligand binding promotes access to src family Tyr kinases (SFK's)
  • conformational change of antigen receptor complex upon ligand binding exposes ITAM's to SFK's
Term
Role of CD45 in activating T cell
Definition

stimulate phosphatases that will activate Lck and Fyn (receptor associated tyrosine kinases), which contain tyrosine kinase activity that will produce GEF and PLC

Term
activation of BCR
Definition
  1. CD45 phosphatase activate receptor associated tyrosine kinases stimulate
  2. Syk (tyrosine kinase) binds to phosphorylated Igβ and become activated
  3. activated kinases activate CD19, PLC, GEF's
Term
Role of PLC in signal cascade
Definition
  1. cleave PIP2 into IP3 and DAG
  2. DAG and calcium activate PKC, which activates NFkB
  3. IP3 incrases intracellular calcium, activating calcineurin (phosphatase)
  4. calcineurin activate NFAT (transcription factor)
  5. NKkB and NFAT act to induce specific gene transcription, leading to cell proliferation and differentiation
Term
Role of GEF's in signaling cascade
Definition
  1. GEF's activation of small G proteins
    1. ex: Ras and Rac (bind GTP)
  2. small G proteins activate MAP kinase cascade
  3. Ras-induced kinase cascade induces and activates Fos (component of AP-1) transcription factor
  4. induces specific gene transcription, leading to cell proliferation and differentiation
Term
Mechanism of action of cyclosporin
Definition
  1. blocks the transcription of calcineurium, which will dephosphorylate NFAT
  2. If NFAT still has its phosphates attached, it wont be active
Term
Role of ITIM's
Definition

Recruit phosphatases tp membrane associated immunoreceptors that can inhibit tyrosine kinase based activation pathways.

Term
Two main ways to inactivate receptor cascades
Definition
  • activate tyrosine phosphatases
  • ubiquinylation to degrade signal proteins
Term
Enzyme that degrades signaling proteins? What happens if this enzyme is not active enough?
Definition
  • Cbl (ubiquitin ligase)
  • if you do not have enough inhibition of cascades, it can cause autoimmune diseases
Term
Various cell to cell interactions that can regulate activation of immune cell cascades
Definition
  • co-stimulatory molecules
  • cytokine receptors
  • pathogen recognition receptors (ex: toll like receptors)
Term
Costimulatory signals seen in naive T cells
Definition

CD28 interacts with B7 to promote:

  • cell survival/protect from apoptosis
  • IL-2 production leading to proliferation
  • cytoskeletal rearrangements, raft recruitment
Term
Signals delivered by APC that affect T cell activation
Definition
  • activation
  • survival
  • differentiation
Term

Describe the phenomenon of inside out signalling that occurs in T cells

Definition
  1. T cell initally binds APC thru low affinity LFA-ICAM interactions
  2. subsequent binding of TCR's signals LFA via adhesion and degranulation adaptor protein (ADAP)
  3. conformational changes in LFA increase affinity and prolongs cell-cell contact
Term
Role of CD40 in signal transduction
Definition
  • It serves as a co-stimulatory signal which is needed for
    • Ig isotype switching
    • germinal center formation
    • memory
    • macrophage activation

ALSO gets help from T cell derived cytokines 

Term
How are cytokines and chemokines receptors grouped into superfamilies?
Definition
based on structural similarities
Term
mechanism of action of JAK/STAT signaling pathway in cytokine receptor signaling
Definition
  1. cytokine binding dimerize receptor, bringing together cytoplasmic JAK's which activate each other and phosphorylate the receptor
  2. TF's (STATS) bind to phosphorylated receptors, and are in turn phosphorylated by activated JAK's
  3. phosphorylated STATs form dimers that translocate into nucleus to initate new gene transcription
Term
What popular mechanism do chemokine receptors use when activated?
Definition
G protein coupled mechanism
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