Degradation and Remodelling of the Extracellular Matrix

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					     Degradation and Remodelling of the Extracellular Matrix

Serin-Proteases
       -   plasmin
       -   thrombin                specific
       -   t-PA
       -   urokinase

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


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

                             urokinase receptor
                                   (uPAR)
                                                    urokinase
                                                                      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

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

Gelatinasen
 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

Stromelysine
  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

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

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

a
    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:



                                                  hemopexin-domain

                                                      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
   cells.