| ||INVOLVEMENT OF EXTRACELLULAR TEMs IN POLICING STEPS OF ANGIOGENESIS|| |
|general context signaling
- extracellular signaling factors:
- TGFbeta3= TEM39
- Dkk-3= TEM4
- Transforming growth factor beta3 (TGF beta3, TEM39) is essential in endothelial-mesenchymal transformation. It is known to increase proteolytic activity, collagen deposition, and cellular proliferation.
- Dkk-3 (TEM4) is proposed to antagonize Wnt action. The rat orthologue of Dkk-3 is an essential iodothyronine binding subunit of D2, a membrane-bound deiodination enzyme involved in tissue-specific modulation of thyroid hormone action. In the nervous system, thyroid hormones are involved in the interpretation of guidance cues during migration. As the steroid-thyroid hormone superfamily is involved in the regulation of the transforming growth factor-beta system, a functional link between TEM39 and TEM4 upregulation is not excluded.
|INVOLVEMENT OF TEMs IN EXECUTIVE STEPS OF ANGIOGENESIS AND THEIR REGULATION|
|ECM- & BM- deposition and remodeling
- proteases and inhibitors
- ECM deposition
- protease inhibitors:
- (basement membrane) BM deposition
- Collagen I alpha2= TEM10= TEM20= TEM40
- Collagen VI alpha3= TEM12
- Collagen III alpha1= TEM15
- Slit-3= TEM27
- Collagen XII alpha1= TEM36
- lumican= TEM37
- Collagen I alpha1= TEM23=TEM38
- BMP-1= TEM25
- nidogen= TEM11
- Collagen IV alpha1= TEM31_1= PEM59
- Collagen IV alpha2= PEM14
- BMP-1= TEM25
- MMP-2 (TEM7) contributes to endothelial cell invasion by degrading extracellular matrix barriers and by triggering signaling pathways that promote or stabilize the angiogenic phenotype. MMP-2 has been shown to degrade gelatin, laminin, and nidogen, native type I collagen, to activate proteolytically MMP-9 and MMP-13, and to modify biological functions of ECM proteins and, thus, influence endothelial cell behavior.
MMP-11 (TEM6) is potentially involved in remodeling of the extracellular matrix, though matrix degradation by MMP-11 is less efficient. Additionally, MMP-11 may function through release of growth factors from the ECM.
- Cystatin (TEM14) is a cysteine proteinase inhibitor regulating the activities of cathepsins. Indications for its functional role in angiogenesis are circumvential: cathepsins B, H and L have been shown to participate in processes of tumor growth, vascularization, invasion and metastasis.
- COLLAGENS: Interstitial collagens like type I (TEM10= TEM20= TEM40, TEM23=TEM38) and type III(TEM15) are major constituents of the extracellular matrix (ECM) supporting body structure. FACIT (fibril-associated collagens with interrupted triple helices) collagens such as type XII (TEM36) associate with the surfaces of fibril collagens and modify their interactive properties.
- BMP-1 (TEM25) is involved in the processing of the fibrillar matrix components type I-III procollagens and, thus, facilitates fibrillar collagen matrix assembly.
- Slit3 (TEM27) is proposed to be involved in mediating protein-protein and ECM-protein interactions in cell migration by linking multiple ligands.
- Lumican (TEM37) functions in collagen fibrillogenesis by regulate interfibrillar distances and, thereby, establishing the exact topology of fibrillar collagens in tissues.
- The major molecular constituents of basement membranes are collagen IV, laminin, nidogen, and proteoglycans. Collagen IV alpha1 (PEM59, TEM31_1) and alpha2 (PEM14, 4-5 fold upregulation in tumor endothelium) molecules form a cross-linked tight network.
- Nidogen (TEM11) bridges laminin (nidogen-G3-domain mediated) and various other components to type IV collagen (nidogen-G2-domain mediated). It is considered to be essential for positioning during axon migration.
- BMP-1 (TEM25) is involved in the processing of the basement membrane component laminin 5 and, thus, facilitates fibrillar collagen matrix assembly.
- protein fragment of extracellular domain containing proteins (TEM19, TEM41)
- The partial sequence of TEM19 is hinting on a transmembrane or extracellular protein with relation to adhesion.
- The deduced TEM41 is fragmentary. From the known segment the protein is proposed to be extracellular.
- undetermined protein sequences (TEM3, TEM18, TEM26, TEM29, TEM32, TEM33, TEM34, TEM43, TEM44)