Chapter 7: Lymphocyte Receptor Signaling

Question 1

What do signals from antigen receptors stimulate?

Answer 1

• Reorganization of the cytoskeleton
• Activation of transcription factors
• Synthesis of new proteins
• Results in nondividing naive lymphocyte

Question 2

How does an extracellular signal illicit a response inside the cell?

Answer 2

• Transmembrane receptors convert extracel. signal into intracellular biochemical event
• Intracellular multiprotein receptor complexes transmit the signal through many pathways

Question 3

What is the order of lymphocyte signal transduction?

Answer 3

• Tyrosine kinase is activated
• Adaptor proteins are modified recruiting lipid kinases to receptor complexes
• Signal amplification by activating GTPase,serine/threonine kinases, protein phosphatases
• Transcription factor activation, cytoskeletal changes, increase in cellular adhesion and metabolism which all Activate T and B cells

Question 4

How does signal strength relate to TCR signaling?

Answer 4

Signal strength determines magnitude of cellular responses
- Affinity of receptor for ligand
- Abundance of ligand
- [intracellular signaling components]
- Positive and Negative feedback pathways

Question 5

What do tyrosine kinases do? What happens to ITAMs?

Answer 5

• Lymphocyte receptors have no intrinsic enzymatic activity
• By associating with intracellular tyrosine kinases they can initiate signals
• TKs phosphorylate tyrosine residues called ITAMs (immunoreceptor tyrosine-based activation motifs)

Question 6

How do coreceptors work with tyrosine kinases?

Answer 6

• TCRs and co-receptors combo with MHC complexes by binding peptides recruits Lck to phosphorylate ITAMs
• TK ZAP-70 binds to phosphorylated ITAMs through SH2 allowing ZAP-70 to be phosphorylated by Lck
• ZAP-70 then phosphorylates other intracellular signaling molecules

Question 7

What happens when phosphorylation of ITAMs occurs by Src family kinases?

Answer 7

• Members of Src: Fyn, Blk, Lyn
• Syk binds to phosphorylated ITAMs of Ig beta chain
• Syk are close and thus via transphosphorylation initiate further signaling

Question 8

How is intracellular signaling mediated?

Answer 8

• Large multiprotein signaling complexes
• Assembly of multi-subunit signaling complexes involves the binding of signal molecules via protein interaction domains

Question 9

What do adaptor and scaffold proteins do? What are some example proteins?

Answer 9

• Lack enzyme activity but recruit signal proteins into complex before being phosphorylated
• Ex. LAT, SLP-76, Gads, ADAP

Question 10

What four signaling molecules can be activated by phosphorylation of LAT and SLP-76?

Answer 10

• Akt, PLC-gamma, VAV, ADAP

Question 11

Can PIP2 recruit signaling molecules? What does Ca2+ do?

Answer 11

• PIP2 + PI3-kinase = PIP3 which can recruit signaling molecules leading to a modification of membrane lipids
• Ca is secondary messenger, amplifies signal, activates proteins

Question 12

What does GTPase do?

Answer 12

• Bound to plasma membrane and functions to recruit signal proteins and activate them
• Often a signal will travel and activate a molecule to turn on or off a transcription factor

Question 13

What do kinases and phosphatases do?

Answer 13

• Propagate a signal by activating or inactivating components of a pathway

Question 14

What does recruitment of ADAP to LAT: Gads:SLP-76 do?

Answer 14

• Activates integrin adhesion and aggregation

Question 15

What proteins are associated with B-cell?

Answer 15

• Coreceptors: CD19, CD21, CD81 enhance the signal
• SLP-65 adaptor protein
• PI3K-lipid kinase

Question 15

What does recruitment of Vav to the LAT:Gads:SLP-76 complex result in?

Answer 15

• Induces activation of Cdc42 leading to actin polymerization

Question 16

How is a signal terminated? Why must it be terminated?

Answer 16

• Protein phosphatases shut down signaling
• Phosphorylated proteins recruit ubiquinated ligases (Cbl) targeting them for degredation
• Membrane receptors are ubiquinated then transported to lysosome for destruction
• Must be terminated to avoid autoimmunity or cancer

Question 17

How do inhibitory receptors on lymphocytes down-regulate immune response?

Answer 17

• Recruiting protein or lipid phosphatases

Question 18

How can B cells monitor the level of antigen specific antibodies in the environment?

Answer 18

• Immune complexes are poor at activating naive B cells, because of coengagement with inhibitory Fc receptor
• Recruitment of phosphatase SHIP results in PIP3->PIP2 which can recruit Vav,Btk, and PLC-gamma