Integrins and extracellular matrix are thought to transmit signals in two fundam

Question

Integrins and extracellular matrix are thought to transmit signals in two fundamentally different ways. Please explain to me these two fundamentally different modes of ECM mediated signaling. What processes and/or activities need to occur in cells in order for these two distinct signaling mechanisms to operate? Include in your answer a minimal list of actual proteins necessary for these signaling pathways to operate and how they contribute to the signaling mechanism.

When answering this question, think back to what we have done all semester long when discussing a cellular process (like nuclear import or membrane trafficking, etc.), and how we talked about the problem in general terms and then assigned molecules to the various subprocesses.

Explanation / Answer

ECM as the organising center for growth factor receptor signal ragulation

ECM proteins play crucial and complex roles during surface receptor signalling. First of all,ECM serves as a reservoir for growth factors. ECM- bounds growth factors could be released locally and bind to their canonical receptors. Many ECM proteins have binding sites for both cell adhesion and growth factors, allowing local concentration of the growth factors near to their cell surface receptors and cell adhesion sites. This localisation of growth factors, and thus their singnalling, by the ECM probably contributes to the establishment of gradients of the soluble, diffusible growth factors morphogens, which play vital roles in patterning in developmental processes. Such example include fibroblast growth factors(FGFs) and vascular endothelial growth factors(VEGFs)both of which bind toHSPG and can be cleaved off from the glycosaminoglycan components of HSPG by the enzyme heparanase and releasedas soluble ligands.ECM - bound growth factors do not have to be released in soluble form ti function. In fact it is well established that FGFs actually bind to their receptors with HS as a cofactor, with the HSPG 'presenting' these ligends during signalling. other examples are FN and vitronectin, both of which bind to hepatocyte growth factors(HGF) and form complexes with Met (the HGF receptor) and integrins, either positively or negatively regulating the functions of the diffusible morphogen HGF.In this regard ECM can also function as an organising center of the sinnalling complex on the cell surface.

The binding of ECM with growth factors often involves specific domains of ECM proteins and results in modulations of signalling activities. For instance, Fnlll domains in both FN and tenascin-C bind to VEGF, which potentiates the VEGF- mediated signalling through its receptor VEGFR2. Fnlll domains of ECm -associated protein anosmin-1 are shown to bind the FGFR1 ectodomains are functions as a co -ligand for FGFR1 signal complex, enhancing or inhibiting the activity. Similarly, Drosophila collagen IV binds to Dpp, a bone morphogenetic protein(BMP) homologue, and enhances interaction with BMP receptors.Collagen ll, the major collagen of cartilage, contains a chrodin - like VWC domains, which binds to transforming growth factor andBMP-2 acting as a negative regulator for these essential chondrigenic growth factors . On the other hand , some intrinsic domins within ECM protein can act as non- canonical ligands for the receptors. Many ECM proteins including laminin, tenascin, thrombospondin, and fibrillin contain epidermal growth factor like domains which can directly bind to EGF receptor as soluble ligands and modulate its signalling. Fnlll domines of NCAM bind directly to FGFR1 and can induce induce ligand- independent receptor phosphorylation. however, further investicationis needed to determine if there is any difference between the ECM - associated growth factor - like ligands and the canonical ligands in terms of the specific signalling outcome.

Integrin and growth factor receptor signalling

Integrins can activate several signalling pathways independently, but more frequently they act synergistically with other growth factor receptors.Such examples includes insulin receptor type1; insulin -like growth factor receptor; VEGF receptor ,HGf receptor,platelet -derived growth factor receptor and EGF receptor. The functional activities of these growth factor receptors are dynamically requires the presence of specific intergrin subunits and that different cell types express different profiles of integrins may constitute the cellular context determining the outcome of the growth factors signal.

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