Growth Receptors

Cell replication is a highly controlled process and uncontrolled cell replication leads to cancer. Some cells replicate often while others never do. The type of cell determines when and how often it replicates. Some cells like GI tract and immune cells replicate often. They have a very high turnover rate. Many cells only replicate when necessary. This happens when there is damage or injury that destroys those cells. Then new cells are created to replace the missing cells.

The basis of the process is that one cell creates a growth factor in response to injury or an event. The growth factor binds to the growth receptor on another cell which then begins the process of replication. The growth receptor is the first place where genetic mutations can cause cancer. The receptors are proteins that are encoded in the DNA. Mutations in that protein receptor can alter its function. Some mutations lead to an always on effect of the growth receptor. This means the receptor no longer needs the growth factor to become active. Other mutations lead to many copies of the growth receptor. This causes over stimulation of the cell to replicate. Every cell has a growth factor receptor, but not every cell has the same growth factor receptor.

Growth receptors come in families. These families will be used in different tissues. That way a growth signal from one tissue doesn't stimulate growth in another tissue. Some tissues will share some of the same growth receptor families. This is why you will see them in specific types of cancer.

The first major growth receptor is the EGFR family which plays a major role in lung cancer and a smaller role in other cancers like glioma or Head & Neck cancer. EGFR stands for Epidermal Growth Factor Receptor. It is also known as Erb or HER (Human Epidermal Growth Receptor). These 3 names are used interchangeably. In lung cancer EGFR makes up about 10% to 15% of the mutations. There are 4 isoforms of EGFR which are EGFR 1-4 or HER 1-4. When in lung cancer, we call it EGFR. In breast cancer HER2 makes up about 15% to 20% of breast cancer. There are 2 very common mutations in EGFR lung cancer to help develop understanding of how mutations in the receptor can cause cancer. The first is the Exon 19 deletion EGFR cancers. They make up about 47% of the EGFR mutations in lung cancer. The other major mutation is the Exon 21 L858R substitution mutation. There is another 12% that makes up many other smaller mutations. There are drugs developed to target the blocking of the EGFR receptor. This helps stop the aberrant signaling that drives cancer. Often treatment with a drug targeting these mutations leads to new mutations which get around the inhibition of the drug. For example, EGFR inhibitors often lead to T797M mutations. This leads to resistance.

Next up is VEGFR which stands for Vascular Endothelial Growth Factor Receptor. There are 4 isoforms from VEGFR 1-4. They have different roles in different areas of the vasculature. VEGFR inhibitors have a role in wet AMD to block new blood vessel formation. It has been used in oncology to block new blood vessel formation that helps cancer grow.

Another growth factor receptor is FGFR. It stands for Fibroblast Growth Factor Receptor. This one comes with a high level of toxicity as it affects things like the skin. There are some FGFR inhibitors out there, but they tend to have high toxicity. I know Relay is working on a FGFR2 inhibitor that is designed with low toxicity developed using AI and ML. This is in clinical development for Cholangiocarcinoma and some other FGFR mutant cancers.

Another important growth receptor is the PDGFR. This stands for Platelet Derived Growth Factor Receptor. This has a role in GI cancers. These are some of the major growth factor receptors that can mutate and cause cancer in various tissues. There are some smaller ones like MET, KIT, ROS1 and ALK. These tend to play a role in some cancers like MET in Kidney cancer. KIT plays a role in Systemic Mastocytosis and Blueprint is working on drugs for this proliferation disorder of mast cells. ROS1 and ALK play a role in lung cancer for growth receptors. Another small one is NTRK which is a growth receptor in Neurological cancers.

Some of the mutations in these growth receptors are single base substitutions. Others are amplifications where the gene is copied many times. Others are rearrangements of the gene. Some are fusions of two genes. There are many ways these receptors can mutate that lead to over activation of the growth pathways. Blocking that signaling can help fight these cancers. Next we will look at the 2 major growth pathways these growth receptors activate no matter which cell the receptor belongs to. There are many growth receptors, but a few key pathways they activate.

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Growth Pathways Overview

Now we are going to look at the two major growth pathways that take the signal at the growth receptor and translate it into actions by the cell through activating key genes. These two pathways are called the MAPK (Mitogen Activated Protein Kinase) and the mTOR (mammalian Target of Rapamycin). These two pathways both start at the growth receptor and translate that signal to the nucleus through a cascade of activity.

The growth receptor is made up of 3 domains. There is the extracellular domain that binds the protein growth factor. This can be one of the many growth factors we talked about before. The next segment is just the trans membrane spanning region that holds the receptor into the cell membrane. This will be made up of 2 helices of protein. The last part in the intracellular domain which contains Tyrosine phosphate groups.

When the growth factor binds to the extracellular domain, the phosphate inside the cell becomes active. They will bind the first two lead proteins in both the MAPK and mTOR cascades. The GRB2 (Growth Receptor Binding) protein binds to the phosphates as does the PI3K (Phosphoinositide 3 kinase). The GRB2 will initiate the MAPK pathway while the PI3K will initiate the mTOR pathway. You will often hear of SHP2 (Src Homology Phosphate containing domain 2) from companies like Revolution Medicines or Relay as they have SHP2 inhibitors. This SHP2 is a specific domain on both the GRB2 protein and the p85 regulatory domain of the PI3K. They both contain this specific SHP2 domain which allows them to bind to the phosphates on the growth receptor. This initiates these first protein kinases with GRBs and PI3K.

Once these two kinases are bound to the phosphate through SHP2 and active, they will go on to activate the rest of their respective pathway with GRB2 activating MAPK and PI3K activating mTOR. Now that you understand the growth factor receptor pathways with MAPK and PI3K, we will take a look at what they do. Then we will come back to cover each of the pathways in detail.

The MAPK pathway stands for Mitogen Activated Protein Kinase. This activates Mitosis. Its major role is to initiate all the genes necessary for transcription. This is the process of taking the DNA and transcribing it into RNA. The mTOR pathway regulates translation of the RNA into protein. This pathway gets a bit complicated when we dig into it because it needs to monitor both the growth pathway for a signal to grow, and it needs to monitor the nutrients in the cell. This is to ensure there are enough amino acids and energy to make the proteins. It monitors the energy through another pathway called AMPK.

All cells break down glucose to create ATP which powers the cell. As ATP is used, the cell monitors the levels of energy through the AMPK sensor. This is a basic go or no go signal to the mTOR pathway if there is enough energy to begin mitosis. The other role of the mTOR pathway is to monitor the Lysosomes for the presence of amino acids from the breakdown of proteins. When there are enough amino acids the mTOR complex gets recruited to and bound to the Lysosome showing it has enough amino acids to begin protein synthesis.

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RAS Pathway

Before we dive into this cascade, I want to prefix with a bit of background information on how proteins work. It is important to understand when looking at how the cascade works. The first concept is structure equals function in proteins. Proteins are made of amino acids. Those amino acids are encoded by the DNA. They will fold with each other using static bonds and hydrophobic forces to make a 3 Dimensional shape. The shape determines its function in life.A miss coding of a single amino acid can dramatically impact its function. This is seen in many diseases like Sickle Cell. The next understanding of proteins is they can act on each other. When one protein binds to another, it can completely alter the function of that protein. This concept is used very often in cell signaling. In the growth receptor part, I explained how a growth factor binding to the receptor would change its shape and activate the intracellular portion. This happens very often in proteins.

The other concept of proteins is they can receive or lose a phosphate group. The phosphate groups act like energy to perform work. The adding of a phosphate to a protein can turn it on and allow it to do work. Some proteins get phosphorylated multiple times before they become active. As I go through these pathways, you will see a lot of proteins interacting with other proteins in a cascade that acts like dominos falling.

When the growth receptor becomes activated by the growth factor, it gets phosphorylated. These phosphate groups attract and bind the SHP2 domain of the GRB (Growth Receptor Binding) protein. The SHP2 domain of the GRB2 protein binds to the phosphorylated receptor. Then it becomes active and binds to it another protein called SOS1 (Son of Sevenless). This protein is called a Guanine Exchange Factor. Its job is to assist RAS in activation. When SOS1 binds to RAS it allows it to drop the GDP it is bound to. Now this is where RAS becomes a bit complicated so I will do my best to explain it.

RAS is created bound to GDP (Guanosine Diphosphate). This is an inactive form of cell energy. The active form is called GTP (Guanosine Triphosphate). The big thing to remember is 2 phosphates means the energy has been spent. The 3 phosphates means it is fully energized. The RAS protein is made in a shape that accepts it binding to only GDP. This binding is like a safety. It is like putting a gun lock on a gun. The GDP bound to RAS blocks it from accepting any GTP.

Mutations in natural RAS can sometimes prevent this binding to GDP which can allow it to bind right to GTP which is bad. SOS1 has the job binding to RAS and changing its shape so it can release the GDP and bind to GTP. Once RAS is activated, it will have a short time to do its job before it gets actively turned off. There is a tumor suppressor gene called NF1. This protein's job is to hydrolyze the GTP back into GDP. This is another safety to ensure RAS doesn't stay on and drive uncontrolled growth. NF1 stands for Neurofibromin 1. The loss of this key gene drives a disease called Neurofibromatosis.

A mutation in any of the genes up to this point would result in a gain of function mutation. These are all growth driver proteins that would drive cancer growth if any of the RAS proteins are mutated. Some of them are mutated in the off state and some of them are mutated in the on state. This is one key concept most people don't realize about RAS. Some drugs target RAS in off state and others in the on state. Each type of RAS mutation will be an on or off state mutation. The idea of one RAS drug fixing every RAS mutation doesn't make sense. If the NF1 mutates, you end up with a Loss of Function mutation as you are losing one of the breaks on the process. This leads to more active RAS which drives cancer.

Once RAS is active, it will bind to RAF (Rapidly Activated Fibrosarcoma). RAF is normally created bound to an inhibitor protein called 14-3-3. This 14-3-3 protein actually gets used a lot in pathways to inhibit different proteins. 14-3-3 is bound to RAF blocking its active site so it can not be activated. When RAS binds, it changes the shape of RAF allowing several other proteins to remove the 14-3-3 and activate RAF by phosphorylating it. The first is PP2A (Protein Phosphatase 2A) will remove the 14-3-3 from blocking the activation site. This allows for the phosphorylation of the RAF protein. This allows the RAF to become active. One of the most common forms of RAF is BRAF which plays a huge role in Melanoma. This is the BRAF V600E substitution mutation. This drives cancer growth.

Once RAF is active it will go on to activate MEK (MAPK/ERK Kinase). This is a simple activation kinase that activates both MEK1 and MEK2. Then MEK goes on to activate ERK. ERK stands for (Extracellular Regulated Kinase). This is the final protein to become active in this pathway. MEK will activate both ERK 1 and ERK2. This will go on to active transcription factors that turn on the genes necessary for mitosis. These are transcription factors like Myc, Fos and Jun. This will push the cell into the G1 phase of the cell cycle along with the other growth pathway of mTOR which we will look at next.

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mTOR Pathway

I am going to start by covering the 2 mTOR complexes. Then I will go through the 3 inputs that mTOR monitors. Finally, I will finish up by showing you what mTOR itself controls downstream. The first part is mTOR comes with 2 complexes. They are the mTOR complex 1 (mTORC1) and the mTOR complex 2 (mTORC2). They are not just a single protein as we have seen in other pathways. They are made up of many proteins all working together in a complex. Many of the proteins are shared by both complexes with the main exception of Raptor goes with mTORC1 and Rictor goes with mTORC2. The actual makeup will not be necessary to memorize as knowing them will have no effect on understanding how the pathway works. That means I will not cover each of these proteins in these complexes. Just know that they are made up of about 5 proteins each.

Now that we know the makeup of the 2 complexes, we will look at what resources these pathways will monitor. The first will be energy. All cells produce energy in the form of Adenosine Triphosphate (ATP) through the metabolism of glucose (sugar). This energy is necessary for all work done in the cell. This means the first check for mTOR will be to ensure there is enough energy. This is done through an intracellular sensor called the AMPK pathway. When energy is sufficient in the cell, AMPK will activate mTORC2. When energy drops to low levels, not only will AMPK stop activating mTORC2, but it will actively block mTORC1. This is a go/no go sensor that tells the mTOR complexes if there is enough energy to proceed.

The second resource mTORC1 will monitor is the necessary amino acids necessary as building blocks to make all the proteins that will be required for cell mitosis. Here we have to look at the lysosome where nutrients are broken down. When we eat protein, it is digested into small pieces of proteins. They get taken into the cells by the lysosome and broken down into basic amino acids which become the building blocks of new proteins by the cell. The Lysosomes have a Ragulator protein on their surface. This will look for the presence of specific key amino acids. When they are present, it is assumed there are enough resources to proceed with the activation of mTORC1.

The Rag accessory proteins will then bind to Ragulator and bind the mTORC1 complex to the surface of the Lysosome. Normally, mTORC1 will float freely in the cytoplasm, but if amino acids are present, it binds to that lysosome. Once mTORC1 is bound to the Lysosome and has the release of AMPK, it has 2 of the 3 necessary signals to activate. The last one will be the activation of the Growth Factor Receptor. We looked at these before and now we can tie it into the overall pathway.

We noted before that, when the growth receptor becomes active, it will bind the 2 key proteins that activate the MAPK and mTOR pathways. The PI3K (Phosphoinositide 3 Kinase) will bind its regulatory domain to the active growth receptor by its SHP2 domain. PI3K comes in 4 isoforms with alpha, beta, delta and gamma. The alpha and beta work in all cells. They regulate insulin and glucose uptake. These delta and gamma forms work only in immune cells for activation and growth. Regardless of which isoform is used, the roles are the same. The only difference is the regulatory and catalytic domains of PI3K will differ. You will see things like p85 for the regulatory domain and p110 for the catalytic domain of the PI3K protein.

I won't get deep into these different types of PI3K here. They all do the same thing. The big difference is what cells they do it in. Once PI3K is active, it will do its job which is to add a phosphate group to another molecule called PIP2. PIP2 (Phosphatidylinositol 4,5 bisphosphate) is a molecule made up of fatty acids that is bound into the cell membrane. It has phosphate groups at the 4th and 5th carbons. The PI3K will put another phosphate on the 3rd carbon making it PIP3 (Phosphatidylinositol 3,4,5 trisphosphate). Before we go into the role of PIP3, there is a tumor suppressor gene here called PTEN. Its job is to take the PIP3 and remove that 3rd carbon, restoring it back to PIP2. This allows for short activation of PIP3, and then it gets shut down. PIP3 has the role of activating one of the 2 parts of the AKT protein.

The AKT protein has 2 domains with a regulatory and a catalytic domain. The PIP3 will activate one of these and mTORC2 will activate the other. Since mTORC2 is only active when there is energy present, this acts as a safety. AKT is the most critical protein in this pathway. Its first job is to remove the Rheb protein from mTORC1 while it is bound to the Lysosome which clears mTORC1 to become active. This ensures all things are present before mTORC1 becomes active.

The downstream effects of mTORC1 are to run all the ribosomes and other machinery that is required to build all the proteins necessary for cell mitosis. This makes mTORC1 the master regulator of translation. The final aspect is the downstream effects of the activation of AKT. This goes so much further than just removing the breaks from mTORC1. It goes on to activate the cell cycle by blocking key inhibitory proteins like GSK3 which prevents the cell from entering the cell cycle.

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Cell Cycle

The MAPK pathway will turn on the pro growth genes like AP1 and Myc. These are the factors that push the cell into the cell cycle. On the other side, there are tumor suppressor genes like GSKs that are stopping the cell cycle by blocking Cyclin D.

Before we go into the cell cycle, I want to cover some background of the cell cycle. The cell normally is in G0 phase which means it is not growing. It is doing its normal daily job. When it receives the signals to undergo mitosis, it will go through 4 phases of growth and division. The first stage will be the G1 phase. This stands for Gap 1 phase. This is where the cell prepares all the necessary resources and activates all the right genes to replicate its DNA. Then it hits a checkpoint at the end of the G1 to S phase.

This checkpoint verifies the DNA is good before it copies it. Once it passes this G1/S phase checkpoint, it is in S phase which stands for Synthesis. This is where the DNA gets copied so there are 2 copies of every chromosome. After the DNA is synthesized, it moves into the G2 phase where it begins to prepare for mitosis. This is called the Gap 2 phase of the cell cycle. Here all the DNA is checked to ensure it is good before the cell enters mitosis. At the end of the G2 phase of the cell cycle there is another key checkpoint called the G2 to M phase checkpoint. If all the DNA is good after it has been copied, the cell moves into Mitosis.

The last stage is Mitosis itself. There are multiple steps in mitosis which are not critical to understanding the process. There is one last checkpoint during mitosis called the spindle checkpoint which lines up all the chromosomes before division.

The next big concept of the cell cycle is that it is highly regulated. There are many checkpoints and tumor suppressor genes that are always active and ready to stop the process if anything doesn't look right. All the process of the cell cycle is regulated by Cyclin Dependent kinases. These are active proteins that will do specific roles when they come in contact with different cyclin proteins. The cyclin proteins are not present in the cell until it is pushed into the growth cycle. As the cell cycle plays out, different cyclin genes will be turned on and expressed. They will be active for a specific time and then turned off. This allows some of the same Cyclin Dependent Kinases (CDK) to be active with the different cyclins and perform different roles with each.

Different cyclins bind to the different CDKs. They come together to make one protein with a function. Each combination performs different functions during the cell cycle. This is how the cell cycle moves the process forward. The checkpoints are there to stop the process if anything goes wrong with the DNA.

The cell cycle is blocked by an inhibitor called Glycogen Synthase Kinase 3 (GSK3). This is a tumor suppressor gene. When the growth pathway is activated, the AKT will block GSK3 which takes the breaks off the cell cycle. This allows the cell to enter that first stage of growth of G1 phase. Cyclin D will begin to be made and increase inside the cell. This is the first of the Cyclins that will be made during the cell cycle. It will combine with CDK4 and CDK6. Combined this goes on to phosphorylate another tumor suppressor gene called Retinoblastoma (Rb). Normally the Rb binds to a key transcription factor called E2F and prevents it from entering the cell nucleus where it can activate genes. This is how the cell prevents the cell cycle from starting unless it is required. It has multiple layers of breaks it has to overcome before it can even get started right. So far we had to stop GSK3 to get the cycle started. Then we had to block Rb to get transcription going for genes.

As the Rb is phosphorylated by the CDK4/6, it will cause the Rb to get tagged for degradation. This takes this key inhibitor completely out of play. With the Rb gone, the E2F is now free to move into the nucleus and activate the genes it targets. E2F activates 2 key genes. The first is it starts the next cyclin in the cell cycle by activating Cyclin E. The other thing it does is activate all the genes necessary to do DNA synthesis. This will be genes like helicase and DNA polymerase.

The CDK4/6 activation of Cyclin E pushes the cell in the S phase of the cycle. This is where the DNA will get copied. The Cyclin E will bind to the Cyclin Dependent Kinase called CDK2. Combined they will have 2 roles. The first thing it will do is activate the gene for Cyclin A. It will also activate the genes for the initiation complex. If you studied DNA synthesis, there is an Origin of Replication about every 100,000 bases. There is a group of proteins that bind to the Origin of Replication and form the initiation complex. That is where the DNA polymerase will bind to start copying the DNA. Now we have DNA synthesis going.

Cyclin A will bind to 2 different kinases with CDK2 and CDK1. Yes, here we are reusing CDK2 with a new cyclin. The cyclin A will bind to CDK2 and block all the genes for the initiation complexes. Why? Now that synthesis is started, we don't want it to start again and again. The Cyclin A/CDK2 will stop that from happening. The cell will finish DNA synthesis and the Cyclin A will bind to CDK1. This will push the cell through the G2 phase of growth and to the final G2/Mitosis checkpoint. The Cyclin A/CDK1 will activate the last cyclin that regulates mitosis.

Cyclin B will be the last cyclin to move the cell through the process of mitosis. The Cyclin B will bind with CDK1 and work to regulate the process of the DNA spindles forming and chromosomes lining up on the mitotic plate. A final checkpoint exists once all the chromosomes are lined up before they are cleared to be separated by enzymes and pulled to each side of the cell.

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DNA Repair

DNA repair pathways are not just a single set of pathways. There are different types of DNA damage and there are proteins and enzymes that search for and fix this damage. There are a few basic systems for DNA repair with single base repairs, nucleotide repairs which replace a small segment of a DNA strand, single strand break repair, and double stranded break repair. Even double stranded break repairs have 2 different pathways they can take to do repairs.

The one key difference for the DDR pathways is they are always active. The growth pathways only become active when they are triggered by a growth factor. The DDR pathways are on all the time in the cell. They are always watching and checking the DNA for any signs of damage. This is critical as the DNA does get damaged all day long from events like UV radiation and deamination events. The DNA can have hundreds of deamination events in a single day. There are a few basic pathways that regulate specific types of DNA damage. They fall into Base Mismatch repair (MMR), Base Excision Repair (BER), Nucleotide Excision Repair (NER), Single strand break and Double strand breaks.

The majority of insults to the DNA occur to a single base. These can be things like a miss match during replication. This can happen and be detected during the G2 phase of cell growth. This will initiate a pathway that results in one base being removed and replaced to match. The next type of repair is the Base excision repair. There are many events that can cause a single base to be damaged. Some of the most common are deamination, depurination, and alkylation events. There are enzymes like Uracil DNA Glycosylase (UNG) that will detect the deamination of a base and initiate BER. Another very common one is depurination events. This is when the bonds of the base get cleaved and the Adenine or Guanine gets lost. These depurination events can happen thousands of times a day and need to be repaired by BER. Next up is Nucleotide Excision repair. This typically occurs in UV radiation. What happens is 2 bases become fused together. Since base excision repair (BER) only repairs a single base, it could not fix a fusion of 2 bases from UV light. That is where NER comes in. It typically cuts out the single strand of the DNA for two complete turns. Then it uses the other strand to fill in the removed bases.

One of the most important repair pathways is the Double Stranded Break. This is of importance in gene editing. There are 2 pathways from which a DSB can be repaired. The first is Homology Directed Repair (HDR). The other is Non-Homologous End Joining (NHEJ). Which pathway gets used is determined by the cell. If the cell is going through the cell cycle and there is a second copy of the chromosome present, then HDR repair can be used. This takes the other chromosome and uses it as a template to do the repair on the damaged chromosome. The number of cells being at the right stage of cell mitosis makes this pathway very rare. It is used about 10% of the time on average. The vast majority of DSBs will be fixed by NHEJ repair. This basically takes the 2 ends of the DNA and just glues them back together. It can be inaccurate at times. Sometimes bases can be added or removed during NHEJ. That makes it a very risky way to fix the DNA.

All of these DNA damage repair pathways feed into the cell cycle. They act as protectors of the DNA and will arrest the cell cycle should any damage be spotted. This prevents the DNA from being copied or the cell splitting if the DNA is not correct. This is mainly controlled by a pathway that regulates p53. This protein is known as the Guardian of the Genome. If any problems occur with the DNA, the pathway to p53 is activated. As p53 levels grow in the cell, the first attempt will be to repair the damage. If p53 levels get too high, then the cell will undergo Programmed cell death. One of the main actions of p53 is to activate Retinoblastoma (Rb). We learned in the cell cycle that Cyclin D will remove Rb and allow the transcription E2F to enter the nucleus and activate the genes for DNA synthesis. When p53 becomes active it will activate p21 which then activates Rb. This causes Rb to grow in levels and block E2F thus arresting the progress of the cell cycle. This will not be released until p53 is stopped by the repair of whatever damage was done to the DNA. If DNA repair fails, p53 continues to rise until it activates cell death. This is a method by which many chemotherapy agents work. They damage the DNA so badly that p53 shoots higher and initiates cell death.

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Wnt Signaling

The Wnt signaling pathway is a growth pathway that plays a large role in embryonic growth and development. It is a common growth pathway that gets mutated in some cancers like Colorectal Cancer. The receptor for this pathway is on the cell surface. It is called the Frizzled receptor. It accepts certain growth factors which trigger this pathway to promote cell growth and mitosis. The receptor works when the frizzled receptor is engaged by a growth factor. It will dimerize with another co-receptor called LRP5 or LRP6.

The key protein in the Wnt Pathway is called Beta Catenin. This is a transcription factor that activates key growth genes to push the cell into the cell cycle. The Beta Catenin transcription factor is degradered as fast as it is created by a complex called the Beta Catenin Destruction Complex. That is right. This pathway is held in the off state by a complex that destroys the Beta Catenin protein as soon as it is made.

When the Frizzled receptor is activated, it will recruit the Beta Catenin Destruction Complex to the active receptor thus rendering it unable to destroy Beta Catenin. This allows the Beta Catenin to enter the nucleus and activate the genes to drive the cell into the growth cycle. There are a few proteins in the Destruction complex which are important. The first one is GSK3 which we talked about in the cell cycle. Another is the APC protein called Adenomatous Polyposis Coli protein. This is a common onco gene that mutates in cancer. A mutation in the key proteins of the Beta Catenin Destruction Complex renders the complex ineffective. That prevents it from doing its job of destroying Beta Catenin. These cells will have constant high levels of Beta Catenin driving uncontrolled cell growth.

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T Cell Receptor

The T cell receptor is not just a receptor but part of a bigger complex. If you have studied Immunology, you know the T cell receptor is made up of 2 protein chains called the alpha chain and the beta chain. These chains will bind to antigens presented by the MHC complex. Neither of these chains actually span the cell membrane. They are embedded into the membrane, but they don't go through it. So how is the signal of the T cell receptor binding to antigen passed through the cell membrane to the nucleus? It comes from 2 separate sets of proteins. The first is the CD3 and Zeta chains. They are embedded into the cell membrane around the T cell receptor. They are inside the cell membrane and don't pass outside the cell. So how do they know when the T cell receptor is active? They get help. The CD3 and Zeta chains are intracellular complexes where phosphate groups can be added to activate them, but they never cross the membrane to know what is happening outside the cell. So how does the binding of antigen binding to the T cell receptor reach these CD3 and Zeta proteins inside the cell? They get help from the CD4 or CD8 proteins that are part of the T cell receptor complex. When the T cell receptor binds antigen, the CD4 or CD co-receptor binds to the MHC. This activates their protein domains inside the T cell.

The CD4 and CD8 proteins go through the cell membrane with the intracellular domain having a place where it can be phosphorylated and become active. The activated CD4 or CD8 will recruit a new protein called Lck. Lck has the job of activating all the ITAMS that make up the CD3 and Zeta proteins inside the cell. That is right. The CD4 or CD8 has a key job of translating the binding of the T cell receptor to the activation of the CD3 and Zeta chains.

Once the CD3 and Zeta chains are all active, they recruit a key protein called Zap70. This protein will recruit and activate another key protein called LAT which stands for Linker for Activation of T cells. The LAT protein becomes like a power strip that activates and recruits many other proteins that go on to activate key growth and cytokine pathways. It recruits SHP2 for activation of both MAPK and mTOR pathways. It also activates the pathway for inflammatory cytokines.

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B Cell Receptor

The B cell receptor works much like the T cell receptor in the way it transfers the binding of antigens from the receptor to the inside of the cell. The B cell receptor is just an antibody that is membrane bound. It is embedded into the membrane but does not pass into the inner cell. It only binds to the antigen. The B cell receptor complex has 2 other proteins called IgA and IgB or CD79A and CD79B. These act very much like the CD3 and Zeta chains. They are intracellular domains and have no contact outside the cell. They get their signal from the famous CD19.

The B cell receptor binds antigen, then the CD19 comes and binds to the antigen like a co-receptor. This causes the domain of the CD19 protein inside the cell to become active. It will recruit a protein called Lyn which then will activate all the ITAMS on the IgA and IgB. Once active they will recruit to famous proteins called Syk and BTK. These proteins go on to activate the same growth pathways like MAPK and mTOR. They will also activate the pathways that produce inflammatory cytokines.

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TLR Signaling

Toll Like Receptors are used by antigen presenting cells to find and engulf pathogens. They are key to the primary source of inflammatory cytokines. There are a total of 9 Toll Like Receptors in antigen presenting cells. Five of them are on the cell surface designed for bacteria and four of them are inside the cell for viruses. These 2 different types of pathogens will provoke different cytokine release.

The external pathogens activate the MyD88 and IRAK4 pathway which leads to proinflammatory cytokines like TNF-alpha, IL1-beta, and IL-6. The other pathway starts inside the antigen presenting cell when the internal Toll Like Receptors engage viruses. This will lead to the activation of the IRF pathway which leads to the release of Interferons. These are the key cytokines that activate the antiviral state.

Many of these pathways inside the antigen presenting cells mutate or have genetic variations which leads to their over activation. This leads to their role in inflammatory diseases and even cancer.

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