Lecture 16: The Basal Lamina

The basal lamina The basal lamina is a specialized form of the ECM The same as basement membrane Present in all multicellular animals Underlies all epithelia Surrounds individual muscle cells, fat cells, and Schwan cells (wrap around peripheral nerve cell axons to form myelin) Functions as a selective filter in kidney Other functions of basal lamina Determines the cell polarity Influences cell metabolism Organizes the proteins in adjacent cells membranes Promotes cell survival Promotes proliferation and affects differentiation Serves as a highway for cell migration in regeneration of the epithelium tissue Basal lamina Basal lamina is synthesized by the cells on each side of it: epithelial cells and storms (cells of connective tissue) provide some components The macromolecules that make the basal lamina Fibrous proteins, mostly glycoproteins, which have oligosaccharide chains attached (laminin, collagen and others) Proteoglycans Associated with fibronectin of the connective tissue Connects with epithelial cells through integrins The content of basal lamina varies from tissue to tissue Laminin is the primary organizer of the sheet structure Heterotrimer molecule Glycoprotein Interact with each other, other basal lamina components, and integrins The roles of the main components of the basal lamina Collagen provides basal lamina the tensile strength Laminin is responsible for the sheet structure of the basal lamina Proteoglycans, collagen and laminin are important for the filtering functions Integrins provide binding to the cell membranes How do the cells move inside the extracellular matrix? Cells which need to move secrete proteases Examples: branching growth of epithelial structures, such as glands, migration of WBC out of the blood vessel (need to digest their way through basal lamina) Proteases are spread only locally Many cells have proteases bound to receptors Protease inhibitors are produced where proteases are not needed Integrins Link cells to extracellular matrix (ECM): matrix receptors In ECM, integrins mostly bind to laminin, fibronectin, and collagen Important for epithelial and connective tissue architecture Also important as signaling molecules, which can transmit the signals in both directions From outside to inside about the cell surrounding From inside to outside to regulate the strength of binding to ECM in response to signals Can serve as cell-cell adhesion molecules, bind to Ig-like CAMs Bind with low affinity, strong binding is achieved by integrin clustering Ca2+ or Mg2+ dependent Their affinity can be regulated Ig-like CAMs participate in _____ interactions • A. Homophilic • B. Heterophilic • C. Both Structure of integrins Integrin is a heterodimer: alpha and beta subunits Both alpha and beta are glycoproteins (proteins linked to polysaccharides) At least 24 integrins in humans Hemidesmosome Integrins link laminin outside the cell to keratin filaments inside the cell Which of the following are not Ca-dependent? • A. Selectins • B. Cadherins • C. Integrins • D. Ig-like CAMs Integrin can be in active or inactive conformation In inactive state (not bound to extracellular ligand) the intracellular parts of alpha and beta chains adhere to one another When integrin is stimulated from inside or outside, its conformation changes Alpha and beta chains no longer bind to each other and become available to bind filaments inside and outside the cell Integrin binding to ECM increases its binding to intracellular filaments To regulate the cell movement along the surfaces the integrin binding should be regulated When cell attaches to some outside components, alpha and beta chains move away from each other, exposing the binding site to protein talin that recruits actin filaments As a result, an intracellular network of filaments is formed inside the cell Integrin binding to ECM changes in response to intracellular signals (inside-out regulation) Signal transduction chain in response to thrombin, that is released in blood clotting, activates integrins by recruitment of talin, which serves as an adaptor for actin filaments. As a result, extracellular domains of integrin bind to blood vessel walls and platelets become sticky and aggregate Signal transduction chain is not for memorization Talin binds to _____ domain of integrins • A. Intracellular • B. Extracellular • C. Transmembrane Integrins recruit intracellular signaling proteins at sites of cell-matrix adhesion Focal adhesion kinase (FAK) is recruited to integrins. It results in recruitment and phosphorylation of signaling proteins since FAK serves as a scaffold Examples of regulation of integrin binding activity Platelets are induced to bind to matrix protein fibronectin for blood clotting T-cells binding to antigen activates their integrins to bind and activate other immune system cells During development, when cells should disintegrate from the matrix and migrate Cell-matrix adhesions respond to mechanical forces When there is a pulling force at integrins, talin unfolds revealing the vinculin binding site that results in recruitment of extra actin filaments Integrins activate intracellular signaling pathways Attachment to matrix is important to stem cells When they lose the matrix connection they can’t proliferate (defense from cancer) Some cells (epithelial cells, endothelial cells) die by apoptosis unless they are attached to matrix