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Lecture 7

Lecture 7 - Cellular Signaling.pdf

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Maurice Ringuette

Lecture 7 - Cellular Signaling November 8, 20135:08 PM How cells talk to one another. Moelcular mechanism of cell communication For development and maintenance of multicellular orgnaisms. In addition to multicellular orgnaisms there are uni cellular orgnaisms on earht long time before we were, there were single celled organimss. The question is why did it take so long for multicellular organisms to derive? The singalling for them to establish took long, this is one idea. How do unicellular orgnaisms communicate with one antoher? BIO230 Page 1 Quorum sensing in bacteria: Bacteria can release chemicals into the environment and response to them. Bacterial processes , they can produce antibiotics, form spores, can undergo sexual conjugation and so on. We can go one step up and look at unicellular eukaryotes, yeast. Signaling is required to undergo yerast to mating. Shape changes but happen foe mating to happen. One level in structural complexitiy: Dictosyllium, single cells, (in the blow up), they live in soil. - Crawl around and eats bacteria - similar to how immune cells hunts down and eats bacteria. - Live in soil. Hunting down things in soil. - When they run out of food they signal each other and the single cells aggregate together to the multicellular sdtructure. The mound in the middle forms a frutingbody or mushroom . On top of that they undergo sporulation so they can undergo distribution to u=oter sites where there are bacteris. This shows singalling in all levels of complextiy How cells communicate to develop and maintain complexes in multicellular organisms. Important to know that in complex animals like mammals, flies and worms they have similar communication pathways. Many of the pathways were First discovered mutants in cell communication in simpler organisms where it was easy to study. - Drosophila, c elegans By studyingthem in mics and human disease we can see how the same componenets are important for higher organimsms and human health BIO230 Page 2 Basic level of cellular signalling: There has to be a signal sent from one source to antoher. Basic way of how cells send signals and receive a signal: Cells can send out 100s of different types of signalling molecules. Not just sending information by voice, there are many ways. - They can send proteins, small peptides, AA and even dissolved gases These can be sent out by exocytosis, diffuse out of the PM, through the PM or they can be displayed on the cell surface. There are 2 ways for the cell to receive the signal: The cell has to have some molecule that is going to bind to the signalling molecule. Some kind of Interaction between the signalling molecule and some molecule in the receiving cell so cell can recognize the message and send it downstream. We can have a cell surface receptor (shown in green) Cells need cell surface receptor when the signalling molecule is hydrophilic. Hydrophilic, likes water, It cannot pass through the PM because its hydrophobic. Cell needs a receptor on the outside to interact with the hydrophilic molecule. Instead of detecting the signalling molecule on the outside of the cell it can detect from insode. Other basic way : instead of detecting the molecule from outside cells can detect it fro inside the cell. This only works if the signalling molecule has hydrophobic nature to it so it can pass through the PM on its own to the inside of the cell ane meet the receptor. That means this milecule needs a carrier prtein to carry it though the water. Then little bit of its released and passed through the membrane and binds to the receptor Here is a couple of examples for short term signalling: Contact dependent:" signal is retained on the cell surface. Signalling cell and target cell is shown. Signalling molecule and recieveing molecule are transmembrane proteins. We talkined about it in the Notch signalling pathway. Example : notch signalling • short range signalling. Paracrine signalling. The singalling cell releases a molecule that can diffuse away, but cant go very far. The signalling molecule doesn’t go very far. Only affects the local environment. There is a couple of reasons as to why the signal is restricting the movement of going further: - the signal is internalized from neighboring cells, it gets gobbled up so can't go very further - Signal might be a protein, or small moelcule might be unstable, or detroed by the extracellular space so cant go further - bOund to extracellular matrix moelcules so it cant diffuse away. Gets trapped in the extracellular matrix and cant go away. BIO230 Page 3 This can happen in two ways: Long range singalling in nervous sytem. We can send signal from brain to the leggs/ ars\ms. Etc The distance covered in this is covered by axons. Long range because the cell sends long extentions that runs through out the body like wires. The length of the axon gives the long range ability to find the target cell. Another exaple is endocrine signalling: Endocrine signalling: where the endocrine cells secrete hormones to the blood cell. Endocrine cell, the cell is located only in one location. Doesn’t have projections. What its doing is secreting molecules into the blood stream. Can travel the whole blood system and can reach cells in the system. For a cell to receive a signal the message has to be sent to different machinery in the cell whether its cahnge in gene transcription. Cell structure or cell behavior messgae has to be sent inside. This is called signal transduction. Convertion of extracellular signals into instracellular singaln. Converting one type of signal to a different type of signal. Effectors: When we look at a pathway where we have a signalling molecule binds to the receptor, that is the initial signal. Then its tranduced into signals into downstream moelcuels that eventually leads to changes in metaboism, gene regulation cytosekelton structure. Downstream molecules are called effectors because the upstream proteins have effect on them? In the diagram, the blues onesa re listed as effector protens. But you can view the triange as effector of the square etc. Anything that is downstrean the pathway can be an effector. BIO230 Page 4 There are different types of molecules. Like cAMP. Small molecules - Called second messengers - can be produced in large numbers. - They can bind to targets and change the structure of the target in some way. Large intracellular signalling molecules - Large - Proteins. - Organized into pathways and networks - concept is: binding of one of its proteins to one of its downstream target changes the target in some way. Changes the phosphorylation. Protein coformation., binding properties etc Basic architectural elemnts in a signalling pathway. Extracellular signalling moelcle is binding to the receptopr. The large protein is called the scaffold. Binds to multiple elements of the pathway. it can concetrate mlecules to a certain loaction and can increase the specificity of signalling. Relay: this is where the signals to the sdownsteam moelcuels are in the sma ebasic form, from one step to antoher. Leads to a protein interaction, protein interaction, and phosphorylation event. The basic signalling mechanism is the same BIO230 Page 5 Step 3: Transdcution: change the cell type from one to anotoher.protein interaction events leads to phosphorylation event leading to Relaeas of calcium, production of lipipds or anuthing. The actual signaling mechains is now changed. If its an enzyme that is doing it you can have an enzynme catalyzing phosphorylation events , you can now phosphorylate multiple downstream targets. Now you can have an amplification step where more proeins are afected by signalling. Upto this far it was linear. We have to think of complexity of signalling networkd. We wanna see a complex netwrok where signals can merge, Arrows shows integartion. Coninceidence detector: requiremet for inouts from two or more pathways for the singal to go on. You see an integration in the pathway. This is a requiremtne for inputs from two or more pathways for the signal to go on. This is called coordianting signalling. The opposite of that is the signal spreads out. When it does that it increases the complexity of the response. More different downstream, proteins can get affected by spreading. Finally you have two mehcanisms at the bottom that restricts the signalling. BIO230 Page 6 Two mechainsms that can restrict the signalling: Orange guy is an anchor that can restrict a part of the signal complex to a specific location in the cell. Can patially Restrict signas in one aprt of the cell to antoher. The arrow shown is an inhibitory arrow, t shaped. Every other arrow we talkked was postive. One componetn is activating the next, activation after another. T sjoaed is an inhibitory arriw where the pathway is inhibited, can turn the signal down s …arrow is an inhibitory arrow. We can have; Phosphorylation event..all the binary decisions If you don’t switch off the pathway there isnt much of signalling information. We send signal with a light, so, if we flip it back and off the light is tnred on and off. When its tunred on and off there is more information there. If it was on then it would be just a street light. But if its tunred on an doff you can give more infomration. BIO230 Page 7 Exmaple of Phsophorylation as a switch: - is a Major contribution to cell signalling. - Look the slide Important thing about these kinases is that they have OH groups and they can be phiosphorylated, phosphate groups can be added. We saw it in phosphatidylinositol where the phosphate group was added to make a PIP. Sp the same idea here. We need The OH group is needed for phosphorylation to occur. What happens: The Signal comes in > activates the kinase where it gets energu from the atp and phsophorylates the substrate > goes from off to ON stage >>phisphorylation changes the structure of the protein. Critical thing is its changing the structure of the oprotein. Either its rturning an exzayme from inactive conformation to active conformation or its creating binding site for another molecule that didn’t exist in a non phosphorylation state.,thqts the way information is sent. Bycahnging the poerpty of the moelcule with phsopahte when the moelcule changes its property the signal can be sent out either as an enzymatic activity ot binds to specific donwstream protein or moelcule. Now if this was always on, the cell would adapt to the signal and it wont be useful. So it needs to be turned off. This is done through phsophotases. Kinases turns on, phosphotases turns off. Nother signalling mechins, is via gtp binding proteins.they can be in theGTP/GDP bound state. - There are large trimeric forms - There are small monomeric too - There is Rab small GTPases. They can act as switches to control endosytic trafficking. - Example for small monomeric gtp binding proteins - They have low gtpase activity. - This one over there doenst have gtpase activty by itself. So needs help. There are specific enzymes that catalyzes the hydrolysis of GTP. And specific enzymes that will lead to the exchange of GDP., bump out the GDP allow a new GTP to bind. GTP bound state is the active state. - GTP binds to downstream effectors. and the signal comes in tunrs it on. This is done through acting through GEF and GAPs. a BIO230 Page 8 GEF:
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