Cell Adhesion and Cell Signalling PDF

Cell Adhesion and Cell Signalling I. What is the extracellular matrix? II. How do cells adhere to each other and to the extracellular matrix? BS31004: Biochemistry and Cell Biology 1  Cellular adh...

Cell Adhesion and Cell Signalling I. What is the extracellular matrix? II. How do cells adhere to each other and to the extracellular matrix? BS31004: Biochemistry and Cell Biology 1  Cellular adhesion multicellular organisms depend on adhesion of cells to each other and to the ECM for tissue formation some adhesive interactions are relatively stable: - firm adhesion of muscle cells to each other and to connective tissue of tendons, to transmit force to the skeleton - tight binding of skin epithelial cells to each other and to underlying connective tissue to resist abrasion some cellular adhesions are more transient: - leukocytes binding to endothelial cells lining blood vessels before extravasation into tissues - attachment of cells to ECM during migration 2  Cell junctions Cell-cell (adherens Tight junctions Gap junctions Allow signal junctions, (septate junctions in allow passage of transduction between desmosomes), and cell- invertebrates) seal small molecules cells by forming sites matrix adhesions gaps between and ions of cell-cell contact (actin-linked, or epithelial cells to between e.g. neuronal hemidesmosomes) confer cytoplasm of synapses, immune attach to cytoskeleton impermeability or cells. synapses. Other and transmit physical selective junctional adhesions forces. permeability. can have signalling functions as well as structural role. 3  Adhesion is mediated by families of cell adhesion molecules Cell:Cell adhesion: Cadherins - link to actin cytoskeleton (adherens junctions) - or to intermediate filaments (desmosomes) Ig family members (N-CAM, I-CAM) - signalling junctions e.g. neuronal and immune synapses Selectins - link to actin cytoskeleton (non-junctional adhesions e.g. immune cells and endothelial cells) Cell:Matrix adhesion: Integrins - usually link to actin cytoskeleton (e.g. focal adhesions) - or to intermediate filaments (hemidesmosomes) Transmembrane proteoglycans 6 - link to actin, non-junctional  Cadherins As cells attach to each other diffuse cadherin moves to the cell-cell junctions Epithelial cells expressing GFP-E-cadherin http://www.garlandscience.com/garlandscience_resources/resource_detail.jsf?landing=student&resource_id=9780815341 055_CH19_QTM01 7  Cadherins - family of adhesion proteins which mediate Ca2+ dependent homophilic adhesion cadherins cell 1 cell 2 Hirokawa, N and Heuser, J (1981) JCB 91:399-409 - adhesions individually low affinity, but in combination give strong attachment 8 Different types of cadherins 9 Cell segregation during embryonic development Catenins link classical cadherins to the actin cytoskeleton the extracellular domains of cadherins link together to mediate adhesion the cytoplasmic domains are required for linking to the actin cytoskeleton, indirectly via anchor proteins including catenins ( catenin also functions in signalling, eg Wnt pathway) 11 Gap Junctions Small molecule transfer inorganic ions, sugars, amino acids, nucleotides, vitamins, and the intracellular signaling molecules cyclic AMP and inositol trisphosphate Tight junctions  Immunoglobulin superfamily of cell adhesion molecules extracellular domains made up of multiple Ig-like domains mediate Ca2+ independent adhesion can be homophilic or heterophilic Ig domain Immunoglobulin (antibody) 18  Immunoglobulin superfamily of cell adhesion molecules the T cell receptor is an Ig family adhesion molecule central role in antigen recognition by T cells in adaptive immune response 100’s of Ig-family members PECAM on platelets and endothelial cells, VCAM on endothelial cells 19  Cell-cell adhesion at a synapse presynaptic membrane postsynaptic membrane synapse formation requires multiple types of adhesion molecules join pre- and post-synaptic membranes, anchor components of signalling machinery firmly together localised action of neurotransmitters 20 Selectins cell surface carbohydrate binding proteins (lectins) bind mucin (addressins) – cell surface glycoproteins Ca2+ dependent expressed on white blood cells (L- selectin), platelets (P-selectin), endothelial cells (E- and P-selectin) 21  Cell adhesion molecules allow circulating T cells to home to lymph nodes lymphocytes bind to vascular endothelium in lymph nodes through interaction between L-selectin and vascular addressins 22  Cell adhesion molecules control the recruitment of neutrophils to infected tissues transient, weak interactions between selectins on endothelial and carbohydrate ligands on neutrophils allow the cells to attach to blood vessel wall and roll – slows cells down 23  Cell adhesion molecules control the recruitment of neutrophils to infected tissues integrin Ig-family cell adhesion molecule selectin Ig-family cell adhesion molecule transient, weak interactions between selectins on endothelial and carbohydrate ligands on neutrophils allow the cells to attach to blood vessel wall and roll – slows cells down other adhesion molecules (activated by inflammatory mediators) mediate tight binding and migration into connective tissue 24  Cell adhesion molecules control the recruitment of neutrophils to infected tissues Leucocyte rolling observed directly in an anaesthetized mouse. Artery Vein Tissue http://www.garlandscience.com/garlandscience_resources/resource_detail.jsf?landing=student&resource_id 25 =9780815341055_CH19_QTM02  Selectins are regulated by inflammation some selectins are regulated in response to inflammatory mediators (e.g. TNF, CXCL8, leukotriene LTB4, histamine, thrombin): - upregulation of E-selectin on vascular endothelial cells for neutrophil extravasation - increased cell surface expression of P-selectin on platelets to promote platelet aggregation 26 http://droualb.faculty.mjc.edu/Course%20Materials/Physiology%20101/Chapter%20Notes/Fall%202007/figure_15_06a_labeled.jpg  Syndecans are cell surface proteoglycan adhesion molecules expressed on many cell types e.g. fibroblasts, epithelial cells mediate cell adhesion to ECM bind growth factors (e.g. FGF), cytokines etc 27 Desmosomes  Integrins link epithelial cells to the basement membrane in hemidesmosomes hemidesmosomes are anchoring junctions which link extracellular laminin in basement membrane to keratins within epithelial cells only specialised integrin 64 linker proteins are plectin and dystonin 30 Integrin mediated adhesions 31  Integrins extracellular family of adhesion molecules; non-covalently bound heterodimers mediate adhesion of cells to the ECM physically link intracellular cytoskeleton to the extracellular matrix (e.g. attachment of epithelial cells to basal lamina) cytosol also mediate cell-cell adhesion signal transducing receptors 32 Integrin activation Outside-In signalling: in absence of ligand, dimer adopts folded structure after activation by ligand binding, dimer has extended conformation breaks interaction between cytoplasmic tails, exposing binding sites for cytoskeleton attachment 33 Integrin activation Inside-Out signalling: intracellular signalling (e.g. PIP2 in response to chemokine receptor activation) can activate talin talin competes for binding to cytoplasmic tails, pushing subunits apart extracellular portion adopts extended conformation – higher affinity for ligand 34 Integrin pairs 35  36 ©2006 by The Company of Biologists Ltd Humphries J D et al. J Cell Sci 2006;119:3901-3903 Integrin based cell-matrix adhesion in motile cells Focal adhesions Podosomes F-actin vinculin actin linkers integrin matrix 37 Block, M.R. et al., (2008) EJCB, 87, 491-506 Integrin based cell-matrix adhesion in motile cells Focal adhesions Podosomes F-actin vinculin actin linked cell-matrix adhesions focal adhesions found in many cell types, podosomes resticted to specialised cells of haematopoietic lineage e.g. DC, macrophages, osteoclasts important for signalling, spreading, migration, matrix remodelling/degradation 38  Integrins in cell-cell adhesion integrins can bind other cellular adhesion molecules e.g. Ig-family adhesion molecules L2 39 Summary of cell adhesion molecules 40