Question 1

How do integrins bridge the extracellular matrix to the cytoskeleton?

Accepted Answer

Integrin clusters on the cell membrane temporarily connect extracellular matrix ligands to the cytoskeleton, forming focal adhesion complexes. These membrane-spanning receptors have hydrophobic regions that interact with the phospholipid bilayer. Talin and kindlin proteins activate integrins and link them to actin filaments, creating a structural bridge that enables cell attachment and migration.

Question 2

What role does thrombin play in integrin activation?

Accepted Answer

Thrombin, an extracellular signaling molecule in platelets, binds to G-protein coupled receptors cAR1/cAR3, triggering an intracellular signaling cascade. This activation recruits Rap1 GTPase, which interacts with RIAM to bring inactive talin to the cell membrane. Once talin unfolds and activates integrins, they bind RGD-peptide sequences on fibrinogen, promoting platelet aggregation.

Question 3

How does talin unfold to activate integrins?

Accepted Answer

Inactive talin has its N-terminal head and C-terminal tail domains folded together. When Rap1-GTP-interacting adaptor molecule (RIAM) recruits talin to the cell membrane, binding a phosphoinositide disrupts the head-tail interaction, causing talin to unfold. This unfolding allows talin to activate integrins and link them to other adaptor proteins like vinculin and actin filaments.

Question 4

What is the function of focal adhesion kinase (FAK) in integrin signaling?

Accepted Answer

Focal adhesion kinase (FAK) is a cytoplasmic protein kinase recruited to focal adhesions through adaptor proteins like paxillin or talin bound to integrin subunits. FAK proteins cluster and phosphorylate tyrosine sites on each other, creating phospho-tyrosine docking sites for Src proteins and other signaling molecules. This phosphorylation cascade establishes multiple docking sites for proteins involved in intracellular signaling pathways.

Question 5

How do focal adhesions enable cell migration?

Accepted Answer

Focal adhesions can dynamically grow and shrink, allowing cells to crawl during migration. Integrin clusters form temporary bridges between the extracellular matrix and cytoskeleton, which can be assembled and disassembled as needed. This dynamic nature of focal adhesion complexes permits cells to extend and retract, facilitating directional movement across tissues.

Question 6

What happens when integrins bind signaling proteins directly?

Accepted Answer

Integrins can directly bind signaling proteins and relay signals into the cell through the Ras/MAP kinase pathway. When integrins cluster at cell-matrix junctions, they recruit focal adhesion kinase (FAK) and other cytoplasmic proteins. These proteins undergo phosphorylation, creating docking sites for additional signaling molecules that propagate cellular responses like proliferation and survival.

Question 7

Why are integrins considered both input receivers and intracellular activators?

Accepted Answer

Integrins are integrated into the cell membrane with hydrophobic regions interacting with the phospholipid bilayer. They receive extracellular signals from hormones and growth factors, then activate intracellular response cascades through protein kinases and G-proteins. This dual function allows cells to sense their environment and respond with coordinated changes in proliferation, survival, and adhesion through the cell matrix response to mechanical forces.

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