Saturday, April 9, 2011

Book Notes: ECM Part 1

  • cells utilize two strategies to build up tough tissues and organs (and ultimately, the multicellular organism)
    • extracellular matrix (ECM): network of proteins and saccharides secreted by cells
    • cell-cell adhesion: connecting a population of cells by their internal cytoskeletons
  • tissues come in two types, depending on what strategy of support they use
    • connective tissue: lots of ECM, cells are very scattered in the ECM and attach to the fibrous polymers like collagen rather than to each other
      • examples include bone and tendon
    • epithelial tissue: lots of cells bound in sheets of "epithelia," ECM is just a thin fibery layer on one side of the cell sheet "basal lamina"
      • epithelial cells attach to each other using cell-cell adhesions
  • adhesions come in 4 types
    • anchoring jxns: tether cells together and connect to cytoskeleton, passes along mechanical stress throughout entire sheet through the cytoskeletal fibers
      • adherens cell to cell jxn
      • cell to matrix jxn
      • desmosome
      • hemidesmosome
    • occluding jxns: seal gaps between cells of a sheet to make the sheet also a selectively permeable
      • tight jxn
      • septate jxn
    • channel-forming jxns: make pores where cells connect to share cytoplasm
      • gap jxn
      • plasmodesmata
    • signal-relaying jxns: sites of contact where signals get passed along
      • neural synapse
      • immuno synapse
      • the other types of jxns also can participate in signal transmission
  • epithelial cells line up next to each other, with "apex" side facing the lumenal space (for example, the inside of your intestine) and "basal" side facing the basal lamina
    • from apex to basal lamina, you would find 1st occluding jxns, 2nd cell-cell anchoring jxns, 3rd channel-forming jxns, and finally cell-matrix anchoring jxns where the cell sheet meets the basal lamina
    • transmembrane adhesion proteins: proteins that links the cytoskeleton inside the cell to the ECM or counterpart adhesion protein of another cell to form the anchoring jxn
      • cadherin family mediates cell to cell attachment
      • integrin family takes care of cell to matrix
  • cadherins are calcium ion-dependent adhesion proteins
    • experiment showed they are the main glue: antibodies that blocked cadherins caused cells to separate while antibodies that blocked other adhesive proteins had little effect
    • classical cadherins: closely related in sequence, have 5 cadherin domains on extracellular side
      • includes E-cadherin (epithelium) N-cadherin (nerve, muscle, eye) and P-cadherin (placenta, epidermis)
    • nonclassical cadherins: less related (more deviation in shape, varying number of domains, etc.)
      • take part in specialized gluing (desmosome proteins, special brain jxns, etc) and signaling (T-cadherin doesn't have transmembrane domain, so it doesn't perform gluing function)
  • cadherin binding is homophilic: actin linked cadherin will bind only to another actin-linked cadherin
    • the proteins bind at the N'-terminus tip, where it has a knob and a pocke
    • Let's say cadherin Alice and cadherin Bob want to bind together.  Alice puts her knob in Bob's pocket and Bob puts his knob in Alice's pocket.  :D
    • cadherin proteins have multiple subunits of "cadherin domains" (having a chain of units gives flexibility rather than a stiff rod)
      • calcium ions bind between the domains to prevent flexing and stabilize binding
      • also induces conformational change to increase affinity
      • without calcium, cadherins are easily chewed up by proteases
    • cadherin binding overall is low affinity (compare to signal receptors, who bind tightly with high affinity)
      • strength comes from multiple bonds: cadherins usually group together in a huddle to form a "junction" of multiple cadherins binding their partners on the neighbor cell
      • can be disassembled by peeling them apart like a Velcro strip
  • know Table 19-2 (pg. 1135) for the 4 types of anchoring jxns and the proteins that make up the jxns
  • while cadherins do glue cells together, they do it specifically (exist hundreds of different cadherins for this purpose)
    • birds of a feather stick together (I guess biology likes segregation)
    • a heterogeneous mix of cells from different organs reassociate into segregated sections
    • this function is especially important for development: cell types migrate long distances toward chemicals or down chemical gradient (chemotaxis/repulsion) or by touching cells who signal where to go (contact guidance)
      • at the destination, cells have to recognize it is the destination and associate with destination cells
      • example is cells from neural crest spreading away to form neural network (so that you can feel your fingers and toes!)
  • changing cadherins on your surface changes who you associate with: strategy used in development for migrating cells to bind to origin, and then change cadherins to bind to destination
    • example: neural cells have N-cadherin, but they lose it in order to migrate away from neural crest and gain cadherin-7 to stay loosely together as a group
    • when they get to destination, they lose cadherin-7 and re-express N-cadherin to tightly bind to each other and make a ganglion
  • cells can switch between being mesenchymal and epithelial cells
    • mesenchymal cells are unattached cells that are scattered around tissues: by expressing adhesion proteins, they come together to form sheet of epithelium
    • epithelial cells can remove adhesion proteins and float away
    • 3 regulatory proteins are in charge of this: Twist, Slug, and Snail.  Expressing these proteins swap cells to mesenchyme, turning off these proteins swap cells to epithelium
    • malignant cancer is a form of over-expressing the transition to mesenchymal so that they float away to infect other places (metastasis)
  • linking cytoskeleton to cadherins requires adaptor proteins: alpha-catenin, beta-catenin, gamma-catenin (plakoglobin), p120-catenin
    • p120 regulates assembly of whole adaptor complex: removal of p120 results in cadherin degradation
    • linking to actin is also important to cell-cell adhesion: removal of cytosolic domain of cadherins prevents actin-binding and results in weak cell-cell adhesion (more easily pulled apart)
  • adheren jxns coordinate movement of entire cell sheets (to fold tubes like the digestive system or pinch off into organs)
    • adhesion belt: adheren jxns close to apex side of all cells in a sheet connect to contractile bundles of actin within each cell
    • when all the actin in the belt contracts, the whole sheet curls up like my cat (He likes to lie on his back on the cool tiles in the summer, exposing his fluffy belly; when I reach down to scratch the fluffiness, he curls his whole body and hides the fuzz.  One day, I'll be able to pet him on his belly!)
    • myosin handles actin contraction (remember muscles contracting?)
    • sheet lies flat without contraction
  • desmosome jxns provides strength, no motion (because IFs don't have motor proteins)
    • cadherins include desmoglein and desmocollin, whose tails bind the adaptors plakoglobin, plakophilin, both of whom associate with desmoplakin
    • the adaptors form a thick plaque where IFs bind (not at tips of filaments but along sides of filaments)
    • bind mostly to keratin and desmin intermediate filaments
    • desmosomes create network of strong and stretchy IF bundles throughout epithelium

pg. 1131 - 1144 (from Chapter 14)
jxn = junction
IF = intermediate filaments

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