Lecture 15: Cell Junctions

Cell Junctions Cellular interactions hold the cells of multicellular organism together Why are they important? Provide strength of the body Support the shape of the body Providing the way for the cells to exchange signals and nutrients How are the cells of the body held together? Some of the cells are connected to each other Some of the cells are connected to the extracellular matrix (ECM) Extracellular matrix (ECM) Can take different forms: ECM of connective tissue consists of fibrous polymers (collagen, fibronectin, etc.) Basal lamina = flexible, thin mat of a specialized ECM that underlies epithelial cell sheets and tubes Two main ways in which cells in a tissue are held together Cells are attached to the basal lamina and to each other Cells are inside of the extracellular matrix, connections between cells are scarce Several types of cell junctions in small intestine epithelium cells Tight junction seals gap between epithelial cells Adherens junction connects actin filament bundle in one cell with that in the next cell Desmosome connects intermediate filaments in one cell to those in the next cell Gap junction allows the passage of small water-soluble molecules from cell to cell Hemidesmosome anchors intermediate filaments in a cell to extracellular matrix Actin-linked cell-matrix junction anchors actin filaments in cell to extracellular matrix Anchoring junctions Cadherins superfamily proteins link cells together Integrin superfamily proteins link cells to extracellular matrix The two types of cell-cell anchoring junctions Adherins junctions: link actin filaments Desmosome junctions: link intermediate filaments Which filaments form a layer close to the cell surface? • A. Actin filaments • B. Intermediate filaments The similar two types of cell-matrix anchoring junctions Actin-linked cell-matrix adhesions (focal adhesions): link actin filaments to ECM Hemidesmosomes: link intermediate filaments to ECM Cell proliferation signals are mostly transmitted through ______ • A. Integrins • B. Cadherins Cell-cell anchoring junctions are mostly mediated by cadherins Transmembrane proteins Mediate most of the cell-cell junctions Present in all animals Depend on Ca2+ Cadherins = Ca2+ + adherins There are hundreds of different cadherins Each vertebrate cell expresses one of more cadherins, according to the cell type Differentially expressed by different cell types and in different tissues Types of cadherins Classical cadherins Named according to the tissues where they were first found, but then were discovered in other places, too N-Cadherin (nerve) P-Cadherin (placenta, epidermis) E-Cadherin (epithelial) Non-classical adherins more than 50 in brain alone The cadherins superfamily Extracellular portions of cadherins contain multiple copies of the cadherin domain Cadherins mediate homophilic interactions Cadherins only bind to the same or closely related subtype of cadherins on other cells Cadherins bind to each other only in the presence of Ca2+ Ca2+ binding leads to the rigid structure of the cadherin domain repeats; cadherins interact In the absence of Ca2+, cadherin molecules become floppy and their interaction fails Many cadherin molecules are arrayed in parallel, functioning like velcro Each cadherin binds by a weak bond, but they form a strong interaction together The junction can be easily peeled apart similar to velcro Mutations in E-cadherin are found in many forms of cancer Most cancers originate in epithelia (normal epithelial cells express E-cadherin) To become malignant cancer cells need to escape epithelia and invade other tissues Cancer cells turns off expression of E-cadherin, which promotes the change of malignancy Mutations in E-cadherins promote _____ • A. Benign cancers • B. Metastatic cancers • C. Both A and B Beta-Catenins indirectly link classical cadherins to actin filaments Intracellular domains of cadherins provide anchorage to cytoskeleton This anchorage depends on cluster of intracellular anchor proteins Central part is played by beta-catenin (also a gene-regulatory molecule in a Wnt/beta-catenin pathway). In the presence of wnt signal, beta catenin is stable in cytoplasm and regulates transcription. It can also become available to form junctions Adherens junctions respond to forces generated by the actin cytoskeleton When cells are pulling away from each other, alpha catenin is stretching, which opens up a domain for vinculin binding, leading to the recruitment of more actin filaments Adherens junctions in epithelia form a continuous adhesion belt Actin bundles are linked into a transcellular network This network can contract through myosin motor proteins, which can lead to folding of epithelial sheet Desmosome junctions link to intermediate filaments Desmosome appear as button like spots Give epithelia mechanical strength Especially abundant in epidermis (upper layer of skin) Hemidesmosomes link intermediate filament networks to extracellular matrix Particular type of intermediate filament attached to desmosome/hemidesmosomes depends on cell type: Keratin filaments in most epithelial cells Desmin filaments in heart muscle