Retta - L21 part 1

Questions and Answers

What role do selectins primarily play in the bloodstream?

Facilitate the migration of leukocytes through the bloodstream.

Regulate the expression of integrins on leukocytes.

Promote stable adhesion between leukocytes and endothelial cells.

Mediate transient cell-cell adhesions. (correct)

Which of the following best describes the primary site of leukocyte trafficking?

Arteries.

Post-capillary venules. (correct)

Capillaries.

Lymphatic vessels.

Which cell adhesion molecules are primarily expressed at the site of leukocyte trafficking?

Integrins and mucins.

E-selectin, ICAM, and VCAM. (correct)

P-selectin and L-selectin.

V-CAM and cadherins.

Which of the following classes does not belong to the major classes of cell adhesion receptors discussed?

Cytokines. Signup and view all the answers

What is the unique function of integrins expressed in leukocytes compared to typical integrins?

They allow interaction with endothelial cell adhesion receptors. Signup and view all the answers

What type of interactions do cadherins primarily mediate?

Calcium-dependent homophilic interactions Signup and view all the answers

Which protein is primarily responsible for the strong adhesion between leukocytes and endothelial cells during extravasation?

LFA-1 Signup and view all the answers

What triggers the conformational change in leukocyte integrins allowing for strong adhesion?

Activation by outside-in signaling Signup and view all the answers

Which molecule is expressed predominantly in nerve cells and plays a major role in nervous tissues?

N-CAM Signup and view all the answers

What is the primary role of ICAM in the immune response?

Facilitating leukocyte migration across blood vessels Signup and view all the answers

Which factor mediates the initial transient interaction between leukocytes and endothelial cells?

Selectin-glycoprotein ligand recognition Signup and view all the answers

What is the primary role of integrins in cell-matrix junctions?

Anchor cells to the extracellular matrix Signup and view all the answers

Which junction is primarily formed by non-classical cadherins?

Desmosomes Signup and view all the answers

What mediates the initial interaction and stabilization between T-cells and antigen-presenting cells?

CAMs and integrins Signup and view all the answers

How do leukocytes achieve transmigration into the brain?

By interacting with endothelial cells via selectins and CAMs Signup and view all the answers

Which of the following proteins is NOT involved in forming tight junctions?

Cadherins Signup and view all the answers

What is the main structural difference between focal adhesions and hemidesmosomes?

Type of cytoskeletal filament they interact with Signup and view all the answers

What is the function of stress fibers in relation to focal adhesions?

Facilitate cell contractility and migration Signup and view all the answers

Which of the following correctly describes immunoglobulin-like CAM proteins?

They play a role in cell-cell interactions Signup and view all the answers

What type of interaction allows the stable formation of integrin heterodimers?

Noncovalent interactions Signup and view all the answers

Which of the following integrins is specifically associated with the formation of hemidesmosomes?

α6β4 Signup and view all the answers

What contributes to the diversity of integrins in the body?

Alternative splicing of RNA Signup and view all the answers

Which ions can integrins bind to that play a role in their activation?

Calcium and magnesium Signup and view all the answers

The majority of integrin subtypes belong to which family?

β1 family Signup and view all the answers

What is the major phenotype outcome of a mutation in the α5 integrin subunit during embryonic development?

Embryonic lethality Signup and view all the answers

Which molecular features are crucial for integrin binding to the extracellular matrix?

Ligand binding sites and adaptor proteins Signup and view all the answers

Which integrins are classified as RGD receptors?

Integrins that bind to fibronectin and vitronectin Signup and view all the answers

In focal adhesions, integrins primarily interact with which structure?

Cytoskeletal actin filaments Signup and view all the answers

Which of the following statements is true regarding integrin receptor classification?

Integrins can be categorized by both α and β subunit associations. Signup and view all the answers

What is the primary mechanism through which integrins undergo activation?

Inside-out activation mediated by regulatory proteins Signup and view all the answers

Which of the following describes the consequence of integrins being unliganded?

They trigger apoptosis known as anoikis. Signup and view all the answers

What is the result of the conformational change in integrins upon activation?

They shift from an inactive bent conformation to an active extended conformation. Signup and view all the answers

How do integrins interact with signaling pathways related to growth factors?

They mediate functional crosstalk with growth factor receptors. Signup and view all the answers

Which regulatory protein is notably associated with the inside-out activation of integrins?

Rap1 GTPase Signup and view all the answers

What is the consequence of a mutation in the 1 subunit of integrins during embryo development?

Early death of the embryo and no implantation Signup and view all the answers

How does a mutation in the 7 integrin subunit affect the muscular system?

Leads to muscular dystrophy Signup and view all the answers

What happens when the 2 subunit in leukocyte integrins is mutated?

Leukocyte adhesion deficiency leading to severe infections Signup and view all the answers

Which integrin is crucial for platelet aggregation during blood clotting?

IIb3 Signup and view all the answers

What type of signaling activates integrins to change from an inactive to an active state?

Both inside-out and outside-in signaling Signup and view all the answers

What is the primary ligand for the 64 integrin, and what is its significance?

Laminin; crucial for skin and epithelial interactions Signup and view all the answers

Which disease is associated with mutations in the 3 integrin subunit?

Glanzmann's disease Signup and view all the answers

What does the interaction between leukocyte integrins and ICAM1 facilitate?

Extravasation of leukocytes into tissues Signup and view all the answers

What is a common consequence of mutations affecting the 1 integrin subunit?

Severe defects in various integrins leading to a range of pathologies Signup and view all the answers

What role does Rap1 GTPase play in integrin function?

Promotes the shift between active and inactive integrin conformations Signup and view all the answers

Which mechanism primarily enhances the adhesion between leukocytes and endothelial cells following transient interactions mediated by selectins?

Interactions between integrins and ICAM-1 Signup and view all the answers

What is the primary role of VCAM in the process of leukocyte trafficking?

Facilitating stable adhesion of leukocytes to endothelium Signup and view all the answers

Which factor contributes to the specific function of integrins expressed in leukocytes compared to typical integrins?

Their interaction with endothelial adhesion receptors Signup and view all the answers

Which class of cell adhesion receptors is NOT typically involved in the adhesion process during leukocyte extravasation?

Collagens Signup and view all the answers

What triggers the expression of cell adhesion molecules like P-selectin and E-selectin in post-capillary venules?

Activation by pro-inflammatory factors Signup and view all the answers

What distinguishes N-CAM from ICAM in terms of their primary expression sites and functions?

N-CAM is expressed mainly in nerve cells, whereas ICAM is found in endothelial and immune system cells. Signup and view all the answers

Which process is initiated by the transient interaction between selectins and leukocyte glycoproteins?

Conformational change in integrins. Signup and view all the answers

Which of the following best describes the additional signaling role of Rap1 in leukocyte interactions with endothelial cells?

Rap1 activates integrins for stronger adhesion and interaction. Signup and view all the answers

What is a key characteristic of cell adhesion receptors that belong to the immunoglobulin superfamily?

They can mediate interactions in a calcium-independent manner. Signup and view all the answers

How do chemokines influence the behavior of leukocytes during inflammation?

They signal through chemokine receptors to activate integrins. Signup and view all the answers

Which statement accurately reflects the role of VE-cadherin in leukocyte extravasation?

VE-cadherin is involved in weakening cell-cell adhesion for leukocyte passage. Signup and view all the answers

What is the role of VE-cadherin in the process of leukocyte transmigration?

Weakens cell-cell junctions to allow leukocyte passage Signup and view all the answers

Which structure is primarily responsible for connecting integrins to actin filaments in focal adhesions?

Actin filaments Signup and view all the answers

What initiates the activation of T-cell receptors during leukocyte adhesion?

Interaction between ICAM1 and LFA-1 integrins Signup and view all the answers

What distinguishes hemidesmosomes from focal adhesions in terms of cellular attachment?

Hemidesmosomes interact with intermediate filaments, whereas focal adhesions connect to actin filaments Signup and view all the answers

Which CAM proteins primarily mediate heterophilic interactions between T-cells and antigen-presenting cells?

Integrins and ICAMs Signup and view all the answers

How does integrin clustering influence cell behavior in the immune response?

It increases the affinity of integrins for their ligands, promoting stronger adhesion Signup and view all the answers

Which of the following correctly describes the primary function of cell-matrix junctions?

Anchor cells to the extracellular matrix and transmit signals Signup and view all the answers

What characterizes the molecular changes that occur during the activation of integrins?

Conformational changes that facilitate increased ligand binding Signup and view all the answers

What is the initial conformation of integrins before activation?

Inactive bent conformation Signup and view all the answers

Which type of apoptosis is triggered when cells are unliganded and not adhering to extracellular matrix?

Anoikis Signup and view all the answers

What critical role does the protein talin have in integrin activation?

Causing structural changes that enhance integrin activity Signup and view all the answers

How do integrins influence cell fate in relation to apoptosis?

They enhance survival pathways when attached to ligands. Signup and view all the answers

Which of the following describes the process of inside-out activation of integrins?

Signaling events initiate in the cytoplasm and alter extracellular domain conformation. Signup and view all the answers

Which of the following correctly describes the interaction sites of integrins?

Integrins interact with both extracellular matrix ligands and cytoskeletal proteins. Signup and view all the answers

What is the role of calcium or magnesium ions in integrin function?

They alter the conformation of integrins for activation purposes. Signup and view all the answers

Which integrin subtype is particularly known for its association with hemidesmosomes?

α6β4 Signup and view all the answers

How many distinct integrins can potentially be formed with the known α and β subunits?

24 distinct integrins Signup and view all the answers

Which of the following integrins is most numerous and described as part of a specific family?

β1 integrin family Signup and view all the answers

Which feature characterizes the binding specificity of RGD receptors?

They recognize a tripeptide motif consisting of arginine, glycine, and aspartic acid. Signup and view all the answers

What impact do defects in integrin genes generally have?

They can cause severe diseases due to altered function or expression levels. Signup and view all the answers

Which integrin would likely play a crucial role in cell adhesion to fibronectin?

α5β1 Signup and view all the answers

Which term best describes the principle behind focal adhesion strength?

Concentration of integrins in clusters enhancing adhesion. Signup and view all the answers

What does 'alternative splicing' refer to in the context of integrin diversity?

It generates variants of integrin RNA affecting function. Signup and view all the answers

What is the primary consequence of a mutation in the β1 integrin subunit?

Failure of embryo implantation Signup and view all the answers

How do mutations in the α7 integrin subunit primarily affect muscle tissue?

Development of muscular dystrophy Signup and view all the answers

What is the primary role of the β2 integrin subunit in leukocyte function?

Allowing leukocyte migration from blood to tissue Signup and view all the answers

What phenomenon occurs due to mutations in the α6β4 integrin subunit?

Severe skin blistering and epithelial defects Signup and view all the answers

What is a potential consequence of the mutation of the β3 integrin subunit?

Glanzmann's disease leading to uncontrolled bleeding Signup and view all the answers

Which integrin ligands are primarily involved in interacting with extracellular matrix proteins?

Fibrinogen Signup and view all the answers

What is a consequence of β2 integrin mutations regarding leukocyte function?

Leukocyte adhesion deficiency Signup and view all the answers

Which signaling process contributes to the activation of integrins promoting conformation change?

Inside-out signaling Signup and view all the answers

What is the effect of the activator Rap1 GTPase on integrins?

Promotes the change to active conformations Signup and view all the answers

What happens to platelets if the αIIbβ3 integrin is not activated?

Failure of blood clotting Signup and view all the answers

Study Notes

Selectins and Leukocyte Extravasation

Selectins facilitate transient adhesion between leukocytes and endothelial cells, crucial for leukocyte trafficking.
Adhesion strengthens through the interaction of integrins with Intercellular Cell Adhesion Molecule 1 (ICAM-1).
Post-capillary venules are the primary sites for leukocyte trafficking, allowing migration into underlying tissues.

Endothelial Cell Adhesion Molecules

Endothelial adhesion molecules such as P-selectin, E-selectin, ICAM, and VCAM are expressed in post-capillary venules.
These molecules respond to pro-inflammatory factors, activating leukocytes and promoting their adhesion to endothelial cells.

Cell-Cell Adhesion Receptors

Cell-cell adhesion receptors are classified into four major groups:
- Immunoglobulin superfamily (e.g., N-CAM, ICAM, VCAM)
- Cadherins (both classical and non-classical)
- Selectins (L-selectin, E-selectin, P-selectin)
- Integrins (expressed in leukocytes for cell-cell adhesion).

Calcium-Independent Cell-Cell Adhesion

Immunoglobulin superfamily members mediate calcium-independent cell-cell adhesion.
N-CAM and ICAM are crucial for homophilic and heterophilic interactions, respectively.

Interaction Mechanisms

ICAM is key for leukocyte adhesion and transmigration across the blood-brain barrier.
Transient interactions via selectins trigger outside-in signaling, activating leukocyte integrins such as LFA-1 (αLβ2).
Chemokines activate leukocytes, enhancing integrin interactions with endothelial ligands, facilitating extravasation.

Sequential Adhesion Process

Leukocyte adhesion occurs in a stepwise process: initial attachment via selectins followed by firm adhesion through CAMs and integrins.
Activation of small GTPases (e.g., Rap1) leads to conformational changes in integrins, enhancing their affinity for ligands like ICAM.

Blood-Brain Barrier Dynamics

The blood-brain barrier comprises endothelial cells, pericytes, and astrocyte foot processes, permitting transient openings for leukocyte extravasation.
Similar sequential interactions occur in the brain, stabilizing T-cell and antigen-presenting cell interactions through integrin and CAM engagement.

Cell-Matrix Junctions

Cell-matrix adhesion receptors (integrins) connect the cytoskeleton to the extracellular matrix, classified into focal adhesions and hemidesmosomes.
Integrins play diverse roles in cellular adhesion and migration dynamics, responding to ECM composition.

Integrin Structure and Function

Integrins are heterodimeric transmembrane receptors, formed by α and β subunits, crucial for stable cell adhesion.
There are at least 24 distinct integrins formed by various combinations of 18 α and 8 β subunits.

Integrin Diversity and Ligand Interaction

Binding specificity varies among integrins; some bind to collagen, laminin, or specific tripeptides (e.g., RGD).
Integrin mutations can lead to various genetic diseases, as seen with α5β1 integrin mutations resulting in embryonic lethality.

Key Disease Associations

Integration of integrin functionality is vital; mutations affecting integrin function or expression can result in severe health issues and genetic disorders.### Integrin Mutations and Effects
Mutations in integrin subunits can lead to various developmental issues, including defects in blood vessels and neural crest formation.
Mutation of the β1 subunit results in early embryonic death before implantation, while α5 mutations allow implantation but lead to incomplete tissue development.
α6β1 integrin, when β1 is mutated, causes phenotypes similar to α5 mutations, but α subunit mutations can result in severe skin blistering due to disrupted laminin interactions.
A mutation in α7 leads to muscular dystrophy due to its expression in muscle cells.

Leukocyte Integrins and Immune Responses

LFA-1 (αLβ2) integrins in leukocytes interact with ICAM1 for cell-cell adhesion, differing from most integrins that interact with extracellular matrix proteins.
β2 integrin mutations cause leukocyte adhesion deficiency (LAD), leading to recurrent infections due to impaired leukocyte recruitment.

Blood Clotting Integrins

α2β3 integrin, expressed in platelets, binds fibrinogen; mutations in this integrin lead to Glanzmann's disease, characterized by excessive bleeding due to lack of platelet aggregation.

Integrin Activation Mechanisms

Integrins exist in inactive and active conformations, with activation involving conformational changes triggered by inside-out or outside-in signaling.
Inside-out signaling influences integrin conformation from the cytoplasm, while outside-in signals act on the extracellular side.
Signals such as Rap1 GTPase activate integrins, allowing for stronger ligand interactions and binding to cytoskeletal proteins like talin and vinculin.

Cell-Matrix Interactions and Survival

Integrins support cell proliferation and survival by recruiting signaling proteins that regulate downstream pathways.
Unliganded integrins can trigger apoptosis, showcasing their crucial roles in cell adhesion and survival.
Crosstalk between integrins and growth factor receptors is essential, influencing processes such as cell migration and epithelial-mesenchymal transition (EMT).

Biomechanics of Cell Adhesion

Integrins cluster to form strong adhesions, enhancing cellular tension and promoting migration or adhesion based on the context.
In cancer, weakened cell adhesion and increased focal adhesion turnover can facilitate tumor invasion and metastasis.

Therapeutic Insights

Some integrins serve as therapeutic targets in cancer treatment, particularly αvβ3, which is involved in tumor angiogenesis.
Inhibiting integrins related to blood vessel formation may reduce tumor growth and metastasis potential.

Mechanobiology

The study of mechanobiology emphasizes the relationship between mechanical forces and cellular behavior, including how integrins mediate responses to these forces.
Changes in tension and contractility due to integrin interactions with the extracellular matrix can trigger both mechanical and biochemical signaling pathways.### Biomechanical Events
Comprise the combination of biochemical and mechanical events that regulate cell behavior.
Mechanical events include pulling forces, traction forces, and tension generated by protein interactions.

Mechanotransduction

Defined as the ability of mechanical events to induce and transduce signals, such as those from growth factor receptors.
Signals are transduced into the cytoplasm through various signaling pathways at the cell surface.

Cellular Dynamics

Both biochemical and mechanical processes are involved in critical cell functions, including migration, proliferation, division, and spreading.

Protein States and Functions

α-catenin: Transitions from a closed to an extended conformation, facilitating molecular interactions that induce mechanical events like tension.
Talin: Remains inactive in closed conformation; becomes active upon extension, mediating interactions between integrins and the actin cytoskeleton to promote mechanotransduction.

Role of Tension

Increased structural tension promotes assembly of cellular structures, while disassembly occurs as tension is reduced.

Force Measurement

Tools exist to quantify forces generated by migrating cells interacting with substrates, reflecting cell contractility and extracellular matrix interactions.
The extent of forces generated correlates with the area of focal adhesions; more integrins lead to denser sensors that reflect extracellular matrix stiffness.

Focal Adhesion Dynamics

Focal contacts and adhesions undergo formation and disassembly, observable through video microscopy over time.
New focal adhesions arise and mature as integrins recruit and cluster, becoming larger and more compact.

Myosin and Actin Contribution

Myosin and actin filaments form contractile stress fibers essential for tension and mechanotransduction processes.

Key Proteins Linking Integrins to Cytoskeleton

Major adapter proteins include Talin, Vinculin, α-actinin, and Kindlins, which mediate integrin interactions with the cytoskeleton, facilitating mechanotransduction.