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Lecture 17

Lecture #17

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Jennifer Harris

Thursday, March 12, 2008 - We ended last day talking abou t collagen, which is one of four types of fibrous proteins, so now well talk about these other three. These fibrous proteins run through the extracellular matrix providing structural support similar to how cables would run through reinforced concrete. - This is the concrete with cables. - We learned how collagen could form these long bundled structures running through tissues, but collagen, its organization can vary with tissue type. You can imagine that for example in a tendon , you may want a whole bunch of collagen fibres to be in parallel to form that tendon structure. Underlying our skin however where it is more of a plane, you would want more of a meshwork of criss-crossed collagen molecules to support our skin. - Dif efrent tis ses cal l for dif frent organiz at i n of col lgen an d the organization of fibrous collagen is regulated in large part by these fibril associated collagens so there are different types listed. - Here is our large fibril of collagen and these here are the non-fibril collagen molecules attached to the side. These will decide whether these fibrils will run in parallel or criss-cross structure. Propeptides after secretion Fibrils Surface of collagen fibrils - These fibril associated collagens are similar to real collagen that forms fibrils except these ones retain their propeptides after they are secreted from the cell. We saw for collagen, these collagen molecules that form fibrils have propeptides on them that blocks their formation into larger fibrils before they go outside the cell. Then those propeptides are removed to make these fibrils but for these fibril associated collagens, they are not removed. These ones do not form fibrils and instead they bind to the surface of the collagen fibrils and reshape and organize them in different ways. - That is one way that the extra cleu l lar matrix can be remo d elld an d organized in a specific way. Protease - Another way is that collagen and other extracellular matrix molecules can also be remodelled is by extracellular proteases. This allows for cells to migrate through the extracellular matrix. - This is a picture right here discussed last day about how this is a fibroblast which is creating these collagen molecules and these fibroblasts and white blood cells and other cells in the connective tissue must be able to crawl around within this tissue. - How do they get through this network of ECM molecules? They can make www.notesolution.comuse of proteases to actually cut these molecules, chop them so they can go through. The action of these protease, this has to be highly regulated so you should note that these molecules, the proteases are secreted from cells in an inactive form, and theyre normally secreted along with inhibitors so you secrete the proteases and also inhibitors of those proteases. Generally you dont want these proteases to work except in very specific circumstances. If you sent out active proteases into the ECM, it would digest the entire ECM and it would be gone. These inactive molecules are sent out into the extracellular space and normally their activity is controlled by binding to the surface of the cell that wants to use them. These inactive molecules will bind to the surface of the cell & therefore be locally activated & very specifically controlled. You have very specific digestion of the extracellular matrix where you need a fibroblast to crawl through it or a white blood cell, etc. Proteases - In addition to these cell types, this is also relevant to cancer progression. As well learn about and as were all aware, we will have a primary tumour and then as cancer progresses, the cells will start to migrate away from that primary tumour to other sites in the body. To migrate from the primary tumour, those cells also have to travel throughthe extracellular matrix. They also make use of proteases to do that. - It is important to know about these proteases because there is the potential to develop drugs to block the ability of cancer cells to travel through the extracellular matrix so you might be able to slow down the progression of cancer, stopping them from spreading through the extracellular matrix. - That is just shown in the cartoon. There is a tumourous cell that is growing and metastasizing, moving through the extracellular matrix. It is doing that here because it has these uPA receptors being expressed so therefore it is recruiting this protease called uPA to the surface of the cell and activating it there. Now this cell will have active proteases coating its surface so when it comes into contact with extracellular matrix, it can chop those proteins up and travel through that extracellular matrix. - On the other side, there is an inactive form of the protease that is being expressed, this is competing away the normal protease so most of these receptors on the surface of the cell are now bound to inactive proteases. You can imagine in this case, this is a mutant form of the protease that outcompetes the normal form but you could also imagine that these yellow molecules could be a drug that could be given to a cancer patient. So you can add a competitor of these active proteases that could compete with those proteases for the receptor, basically bump them off the receptors & now this cell here, it may still grow but it will be much more difficult for it to travel through the ECM becoming more contained in the body, preventing metastasis. (e.g. blood vessels, lungs) - Now onto elastic fibres. These fibres also provide structural support but as the name implies, they are elastic. These are abundant in highly flexible tissues like blood vessels or lungs so that when your lungs expand, they will snap back to their original position; when the blood vessel expands, it will snap back to its original position. - A number of our organs have this elastic property so elastin plays a key role in this because it can recoil after tissue stretching. - In the cartoon, we have the elastic fibre that can be stretched out and then snap back afterwards.
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