Degradation and Remodelling of the Extracellular Matrix

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					     Degradation and Remodelling of the Extracellular Matrix

       -   plasmin
       -   thrombin                specific
       -   t-PA
       -   urokinase

       - elastase                 unspecific
       - cathepsins    *
            *mainly lysosomal, but also secreted proteases
             comprises serine- aspartic- and cysteine cathepsins

   migration of cells though the extracellular matrix:
   protease is concentrated at the leading edge

                             urokinase receptor
                                                                      minimal destruction
                                                                   of the surrounding tissue
    Degradation and Remodelling of the Extracellular Matrix

Matrix metalloproteinases (MMPs)
     large group of zinc-dependent proteases
     belong to the metzincin-superfamily of zinc-based proteases

                                                     conserved zinc-binding
                                                     region of the metzincins
Matrix-Metalloproteinasen und ihre Substrate (Auswahl)

Enzym               alternative Namen           typische Substratea

 MMP-1              Kollagenase-1,              Col I, II, III, VII, X, Pro-MMP-2 u.-9
    MMP-8           Kollagenase-2,              Col I, II, III, Aggrecan
    MMP-13          Kollagenase-3               Col I, II, III, Aggrecan

 MMP-2              Gelatinase A                Gelatine, Col IV, Col I, V, X, EL, Aggrecan, Link-Protein
 MMP-9              Gelatinase B                Gelatine, Col IV, Col V, XI, EL, Aggrecan, Link-Protein

  MMP-3             Stromelysin-1,              kollagene u. nicht-kollagene EZM-Proteine, Pro-MMP-1,-8,-9,-13,
                    Proteoglykanase             E-Cadherin, L-Selektin,
                                                Inaktivierung v. Protease-Inhibitoren
    MMP-10          Stromelysin-2               ähnlich wie MMP-3, schwächer aktiv als MMP-3

 MMP-14      MT1-MMP                            Col I, II, III, FN, Lam, PG
 MMP-16      MT3-MMP                            Pro-MMP-2

 MMP-7              Matrilysin, PUMP-1          EZM-Proteine, Pro-MMP-1,-2 u.-9
 MMP-12             Metalloelastase             Elastin + weitere EZM-Moleküle
 MMP-20             Enamelysin                  Amelogenin

    Abkürzungen: Col Kollagen, FN Fibronektin, Lam Laminin, PG Proteoglykane. Spaltung von Pro-MMPs führt zur Aktivierung
Matrix Metalloproteinases
    family of 25 related, but distinct gene products, 24 found in mammals

    consensus structure:


                                                      regulatory domain
               pro-           catalytic domain   (not present in all enzymes)

    secreted or membrane bound enzymes

  synthetized as inactive pro-enzymes:
   a cysteine residue of the pro-domain binds to the Zn-atom in the catalytic site.

  many members contain a C–terminal hemopexin-like domain which is important for
   the substrate specificity of the enzyme.

    in vivo most MMPs cleave preferentially distict ECM- and cell surface molecules.
Regulation of MMP-activity

   The biosynthesis is under control of growth factors and mediators of inflammation.
    It is upregulated in migrating cells and tumours.
    Unstimulated cells express only low levels.

   The enzymes are synthesized as inactive pro-forms.
    They are activated by
      - Golgi-resident proteses (furins),
      - membrane-bound MMPs or
      - pericellularly

   The activity is regulated by TIMPs (Tissue Inhibitors of Matrix-Metalloproteinases).

 Excess activity of MMPs results in tissue damage.

 Inactive mutants lead to impaired wound healing and impaired tissue remodelling,
  especially during embryogenesis.
ECM degradation and remodelling by MMPs

  Degradation of the tadpole tail
  Regression of uterus und mammary glands after pregnancy
  Uterus changes during menstrual cycle
  ECM remodelling during embryogenesis
  Cell migration

  MMP cleavage of ECM substrates can release ECM-bound growth factors.
  Cleavage of von ECM molecules sometimes leads to fragments that have different
   biological activities from their precursors. For example, cleavage of laminin-5 and
   collagen IV generates fragments that promote cell migration.

  Wound healing
  Lymphozyte extravasation into inflamed tissues

  Excessive ECM degradation during inflammation or degenerative processes results
   in tissue damage.
  Degradation of basement membrane proteins by MMPs allows metastasis of tumour