EXTRACELLULAR MATRIX/ADHESION

Reading: Molecular Biology of the Cell Chapter 19 isrequired reading, except for information pertaining tononmammalian cells, and to embryology.

The lecture is based on this chapter, but will onlycover a portion of the required material, plusadditional information not included in the text.

The extracellular matrix and cellular adhesiveevents have fundamental roles in embryonicdevelopment. Time and effort considerations resultin the exclusion of this area.

Fig. 19-1 Simplified drawing of a cross-section throughpart of the wall of the intestine. Each tissue is an organized assembly of cells held together by cell-cell adhesions, extracellularmatrix, or both.

CELL-CELL ADHESION

Largely self-study: types of cell-cell adhesive interactions

[junctional: occluding (tight), adherens, desmosomes & gap; +

nonjunctional] constituents (plasma membrane and

cytoskeletal, if any) and structures of each type of cell-cell interaction

functional roles of each type of cell-cell adhesion

A Summary of Junctional and Nonjunctional Adhesion

Fig. 19-28

Cell-Cell Adhesion: MajorPlasma Membrane Proteins

Junction Protein family

Tight Occludins & claudins (not in text)

Adhesion Cadherins, e.g., E-cadherin

Desmosome Cadherins

Gap Connexins

nonjunct. Ig-like, e.g., N-CAM

nonjunct. Selectins*, e.g., E-selectin

nonjunct. Integrins*

* cell-cell adhesion in a limited number of cell types

Functions of Tight Junctions Restricts movement

of plasma membrane proteins & lipids between the apical and basolateral membranes

Barrier to diffusion of molecules across the epithelial cell sheet

Fig. 19-3A

EXTRACELLULAR MATRIX (ECM)

Extracellular network of macromolecules

Components secreted locally; organized by cells associated with the matrix

Fig. 19-31

BASAL LAMINA

Flexible, thin mat of specialized ECM

Often termed basement membrane

In close association with cells, as illustrated at right, Fig.19-53.

MAJOR ECM CONSTITUENTS

Hyaluronan Proteoglycans Collagens Elastin Fibronectin Laminin Enactin/

nidogenFig. 19-57 Protein in green, glycosaminoglycan in red.

Plasma Membrane Constituents which Bind to the ECM

Integrins Proteoglycans

Fig. 19-28

INTEGRINS Plasma membrane

heterodimers Have ECM or

surface membrane binding domain(s)

Have divalent cation binding sites

Many participate in linking the ECM to the cytoskeleton

Fig. 19-60

Circ Res 89:211. 2001

Integrins and theirligands

J Biol Chem 275:21785, 2000

J Biol Chem 275:21785, ‘00

PLASMA MEMBRANE PROTEOGLYCANS

Annu Rev Biochem 68:729,’99

HYALURONAN

Fig. 19-35

Disaccharide structure

Fig. 19-34 Relative volumes

Table 19-3 Some Common Proteoglycans

COLLAGENS

A helix comprised of homotrimer & heterotrimer polypeptides (alpha chains)

Major proteins of ECMs Many different alpha chains Multiple structures (involves

cross-linking of chains)– fibrils– network forming– fibril-associated

Fig. 19-40

Table 19-4 Some types of collagen & their properties

Formation of CollagenFIBRILS and FIBERS

Fig. 19-43

Formation of Collagen Networks

Fig. 19-52

COLLAGEN ASSEMBLIES

Ann Med 33:7, 2001

ELASTIC FIBERS Elastin, main constituent Fibers crosslinked to form a network Fibers & network can extend and recoil

Fig. 19-50

MICROFIBRILS

Cover elastin core of elastic fibers Also found in other extracellular matrices Contain glycoproteins including fibrillin

FIBRONECTIN (FN) Extracellular dimeric

glycoprotein Differential splicing Multiple functional

domains– cell binding

• RGD sequence of FN• other specificities

– heparin binding – collagen binding – fibrin binding

Organized into a matrix

Fig. 19-51 A,C

LAMININ Heterotrimeric glycoprotein Basal lamina constituent Multiple binding domains

Fig. 19-55

Binding Domains of Laminin

Self assembly Type IV collagen Heparan sulfate Enactin/nidogen Cell Surface

– integrin– nonintegrin

J. Anat. 193:1, ‘98

Cell Suface Binding Sites

BASAL LAMINA

Fig. 19-56

HEMIDESMOSOMES

Junctions linking the intermediate filaments to the ECM

Constituents include – integrins– other plasma membrane

proteins– cytosolic proteins

Functions include– adhesion– intracellular signaling

Bioessays 20:488, ‘98

Focal Adhesion (Focal Contact or Adhesion Plaque)

Junctions linking actin filaments to the ECM

Constituents include – integrins– cytosolic proteins

Functions include– adhesion– cell signaling

Fig. 16-75B

INTEGIN-ECM SIGNALING

“inside-out” signals (1-3) Biochem J 339:481, ‘99

Curr Opin Cell Biol 11:634, ‘99

Diversity in Adhesive Interactions

Diversity in the major components due to:– differential splicing– post-translational modifications– different gene products

Participation of additional molecules

Matrix Metalloproteases Also termed matrix metalloproteinases,

matrixins, MMPs Enzymes which cleave ECM

constituents, including collagenases Contain a propeptide which must be

cleaved for enzyme activity Multiple mechanisms to regulate MMP

activity, including inhibition by tissue inhibitors of metalloproteases (TIMPs)

Other functional domains

Genes Dev 14:2123,’00

Matrix Metalloproteases

Genes Dev 14:2123,’00

ADAM A Disintegrin And Metalloprotease

Trends Genet. 16:83, ‘00

A disintegrin is a molecule that binds to an integrin.

T = transmembrane domain

Trends Genet. 16:83, ‘00