Extracellular Matrix (ECM) functions

holds tissue together

strength (bone)

elasticity (cartilage)

cushioning (cartilage)

adhesion

envt cues to cells

modulates cell-envt interaction

surface on which cell mvt can occur

reservoir for extracellular signalling molecs

ECM components (4)

collagen

elastin

proteoglycans

multiadhesive matrix proteins

fibronectin

multiadhesive matrix protein

glycoprotein that binds to integrins and other ECM components

laminin

multiadhesive matrix protein

major protein of ECM and basement membrane

perlecan

multiadhesive matrix protein

proteoglycan that binds and crosslinks many ECM and cell surface molecs

Cell-adhesion molecules (CAMs)

cadherins, selectins, integrins, immunoglobulins

intercellular and cell-matrix interactions

cadherins

calcium-dependent glycoproteins, mediate homocytic and heterocytic adhesive interactions

intracellular, transmembrane, and intercellular domains

adhesion can be tight or weak

adapter proteins link cadherins to cytoskeleoton, recruit signaling molecules (ex: alpha and beta catenin)

cadherins and cancer

breast cancer metastasis

1. down-regulation of E cadherin-->dec intercell. adhesion strength-->inc cellular motility (cancer cells can cross basement memb)

2. loss of E cadherin--> E-cadherin-catenin complex degrades, release of signal molecs related to invasiveness

3. N-cadherin (not normally present) upregulated w loss of E cadherin-->tumor growth

Selectins

calcium-dependent vascular adhesion molecules produced by endothelial cells

interactions btw endothelium, leukocytes, inflammatory process

E-selectin, P-selectin, L-selectin

selectin response

foreign substance activates macrophages, cytokines stim endothelial cells, which produce selectins

E & P selectins slow down leukocytes, leading to recruitment.  Leukocytes then enter infected site (extravasation)

E-selectin and breast cancer

overexpression: more positive lymph node metastasis

down-regulation: reduction in adhesion (inc motility)

integrins

transmembrane receptors for ECM components

extracellular, transmembrane and intracellular components

attach to intracellular adapter proteins -- cell growth/motility

bidirectional signal capabilities--transmit biochemical signals as well as mechanical force

intercellular adhesion molecule (ICAM-1)

 member of immunoglobulin superfamily

when E and P selectins slow down leukocytes at site of infection, ICAM-1 carries out tighter adhesion function, stopping leukocytes by binding to leukocyte integrins

facilitates extravasation

leukocyte adhesion deficiency

genetic defect in synthesis of integrin subunit

susceptible to repeated bacterial infections and non-healing wounds bc leukocytes cannot extravasate, migrate or phagocytose properly

integrins and cancer

integrin activation down-regulates E-cadherin, allowing cancer cells to cross basement memb

integrin modulates expression of MMPs which break down matrix components, allowing cancer cells in

VEGF (vascular endothelial growth factor) stimulates vasculature at tumor site

pemphigus

antibodies form against ECM laminin or integrin

blistering of skin