2012 Group 6 Project
|2012 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7 | Group 8 | Group 9|
- 1 Insulin Signaling Pathway
- 2 Introduction
- 3 History
- 4 Structure of Insulin
- 5 Insulin Receptor
- 6 Signaling Pathway
- 7 Normal function
- 8 Abnormal Function
- 9 Current Research
- 10 Glossary & Abbreviation
- 11 Images
- 12 References
Insulin Signaling Pathway
Insulin is a major metabolic hormone present in the body that performs minute to minute important physiological roles in order to maintain glucose homeostasis in the body. It is a peptide hormone secreted by 'islets of Langerhans' (beta cells), located in endocrine pancreas and in combination with the hormone glucagon, it stabilizes the blood glucose level . Other cells in the Islet of Langerhans include:
- Alpha cells which are responsible for glucagon production
- Delta cells which produces somatostatin
- PP cells which are responsible for pancreas polypeptide production
The main function of the insulin signaling pathway is to lower the blood glucose level when glucose is abundant to minimize the effect toxicity glucose can have on cells. In response to high levels of glucose, insulin is secreted from the beta cells which have the effect of increasing the rate of glucose intake by cells as it attempts to maintain homeostasis. In addition, the Insulin signaling pathway also regulates the release of stored (saturated) fat, and prevents the release of adipose cells from the liver after a meal as glucose is readily available. The Insulin signaling pathway is dependent on the detection of Insulin by Insulin detectors found in muscle, adipose and other tissue in the body.
High blood glucose levels are detected as blood passes pancreatic tissue and a small amount of glucose is detected by the matrix of the pancreas. More specifically, the glucose is detected by Beta cells which begins to release the stored insulin which had been produced at an earlier stage. The insulin travels via blood vessels and is distributed to; muscles, liver and fat tissues, signalling the intake of glucose into the cell. The signaling pathway of insulin is initiated when insulin molecules bind to its receptors in the cell surface. The signaling pathway eventually causes GLUT 4 molecules to transport to the cell membrane, enabling the transport of glucose into the cell. The Insulin signaling pathway is of high importance when it comes to regulating blood glucose levels, and body mass index. 
Insulin is widely known as the treatment for a number of conditions including Diabetes Mellitus type 1. The Insulin signaling pathway is essential to human life, and acts as signal for cells in liver and skeletal muscle to store glucose as glycogen. People who experience an abnormal insulin signalling pathway are often diagnosed with Diabetes Mellitus. In 2011, an estimation of 360 million people were diagnosed with Diabetes Mellitus throughout the world, and it is estimated that this number will continue to increase to 552 million by 2030. 80% of Diabetic Patients worldwide lives in low - middle income countries with the number of Type 2 Diabetes patients increasing.
|1922||Discovery of Insulin and first treatment of diabetes by Frederick G. Banting, Charles Best and John Macleod that won Nobel Prize in 1923. But Best, the assistant was not acknowledged as participant of nobel prize. They concentrated on making commercial purified insulin for further treatment of diabetes. |
|1923||Precipitation of Insulin for further commercial use, by Banting and his team.|
|1936||Hagedorn and B. Norman Jensen discovered that the effects of injected insulin could be prolonged by the addition of protamine (arginine-rich, nuclear proteins) |
|1949||An approach was made by Rachmiel Levene that the insulin protein facilitated the glucose into tissues occurring outside liver |
|1958||Amino acid sequencing of insulin protein by molecular biologist Frederick Sanger. He won [The Nobel Prize in Chemistry 1958]|
|1960||Discovery of first enzyme GS (glycogen synthesis), that activates insulin by Villar Palasi and J Larner |
|1963||Activation of Glycogen Synthase by insulin by promoting dephosphorylation by DL Friedman and J Larner |
|1969||Crystal structure of insulin was achieved by novelist Dorothy Hodgkin. [Nobel Prize]|
|1977||The first human insulin was produced from E.coli by Herbert Boyer and further used for commercial use|
|1980||Discovery of Glycogen Synthase Kinase-3 (GSK3) by Embi N, Rylatt DB, Cohen P  while looking for other ways to activate GS, they found a protein kinases that inactivate GS.|
|1985||Discovery of IRS-1 (insulin receptor substrate-1) |
|1985||sequencing of a human cell membrane insulin receptor by Axel Ullrich. His experiment showed that the entire aminoacid sequence of the human insulin receptor precursor was coming from a single complementary DNA clone. |
|1988||Discovery of PI3K (Phosphotidylinositol 3-Kinase)|
|1991||Discovery that insulin activated of PI3K  by Backer, J. M. and others in Brigham and Women's Hospital, Boston|
|1992||Inhibition of Glycogen synthase kinase 3 (GSK3) by insulin  |
|1993||Specific inhibitors of PI3K found to block some of the intracellular actions of insulin    |
|1995||Insulin stimulate protein kinase identified as AKT (aka PKB - Protein Kinase B, which inhibits GSK3  |
|1998-||Serine phosphorylation of IRS-1 causes insulin resistance|
Structure of Insulin
The small peptide hormone insulin with a molecular weight of 5808 Da is secreted by pancreatic beta cells of Islets of Langerhan in the pancreas in response to high levels of blood glucose. It is made up of 51 amino acids, containing 21 amino acids long alpha chain (A chain) and 30 amino acids beta chain (B chain). Two disulphide bonds between A7 and B7 and A20 and B19 connects the A chain to the B chain whereas a disulphide bond between A6 and A11 connects the 2 A chains together via cysteine rich residues. In its stored form insulin is kept stable in the form of a hexameric compound where three insulin dimers come together in the presence of zinc ions, however ones in circulation it dissociates into a monomer and the two alpha subunits bind to two separate monomers.  
The following website shows the 3D structure of insulin dimer [| Insulin Dimer]
Insulin Receptor (IR) is an intrinsic tyrosine kinase receptor that activates by binding to its substrates which can be either insulin or insulin-like growth factors. IR is found in most tissues but its numbers vary from 20-40 in erythrocytes to 200000 in adipocytes and muscle cells. 
IR consists of an extracellular domain which is the alpha-subunit and an intracellular component in the form of a beta-subunit. The 2 alpha and beta subunits interact with each other by disulphide bonds.The gene coding for IR is 150 kilobases long containing 22 exons located on the short arm of chromosome 19. Proteolytic processing of a single proreceptor leads to formation of both subunits. Two different isoforms of the receptor can be created by alternative splicing at the site of exon 11. 
The extracellular alpha domain regulates the tyrosine kinase activity by inhibiting phosphorylation of the beta subunit. Studies have shown that deletion or a point mutation that leads to mutation of the alpha domain relieves the inhibition hence exhibiting the importance of the alpha subunit in regulating the ligand binding. 
The beta subunit contains two structures: the smaller upper connects to the larger upper loop via a single peptide bond. The larger lower subunit contains a juxtamembrane motif that binds to the substrate, the ATP binding site provides energy, the regulatory loop contains three tyrosine sites that phosphorylate and the C-terminus (tail) that contains two more auto phosphorylation sites. Ones the alpha subunit binds to the insulin receptor substrates causing an auto-phosphorylation of various tyrosine domains in the beta subunit.  
Autophosphorylation of the IR causes a range of different signaling pathways that includes activation of PI(3) kinase important for glucose metabolism, the MAP kinase cascade required for cell growth and differentiation and the Cbl/CAP pathway required for transportation of glucose vesicles.
The PI(3) Kinase Pathway
Consisting of two extracellular a subunits and two transmembrane b, linked together by disulphide bonds the insulin receptor detects the presence of insulin which binds to the a subunit. The binding of insulin results in a conformational change, which in turn leads to the autophosphorylation of certain tyrosine residues located in the b subunit  . The phosphotyrosine-binding (PTB) domains of adaptor proteins recognizes the phosphorylation of these residues The PTB domains are members of the insulin receptor substrate family (IRS) , and when phosphorylation of key tyrosine residues takes place on IRS proteins, it is recognized by the Src homology 2 (SH2) domain of the p85 regulatory subunit of PI 3-kinase (a lipid kinase). This in turn leads to the phosphorylation of phsophatidylinositol (4,5) bisphosphate (PtdIns(4,5)P2) by the p110, which the is the catalytic subunit of the PI 3-kinease. The phosphorylation of (PtdIns(4,5)P2) results in the formation of phsophatidylinositol (3,4,5) bisphosphate Ptd(3,4,5)P3. As a result, a downstream effector of Ptd(3,4,5)P3 known as AKT is reqruited to the plasma membrane, which then activates AKT with the aid of protein kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1). After activation, AKT enters the cytoplasm and inactivates glycogen synthase kinase 3 (GSK3) by phosphorylation. The GSK3 then phosphorylates glycogen synthase, a major substrate of GSK3, and therefore promotes glucose storage as glycogen .
RAS-MAP kinease pathway
The Ras-MAP kinase pathway is important for cell differentiation and mitogenesis. The phosphorylated tyrosine residue on the IRS-1 protein interacts with an adapter protein Grb2. Grb2 is then responsible for recruiting an exchange protein SOS from the plasma membrane. IRS-2 or Gab-1 protein stimulates the tyrosine residue on phosphatase SHP2. Both SOS protein and SHP2 are required for activation of Ras. An activated Ras protein in turn causes a step by step activation Raf, Mek and MAP kinase. The MAP kinase is an extracellular signal regulated kinase that modulates transcription factors that leads to cell differentiation and proliferation. 
The CAP/Cbl Pathway
The uptake and utilization of glucose depends on the movement of glucose from intracellular storage locations to the plasma membrane. This trafficking of glucose is conducted by GLUT4 transporter migrating to the cell membrane (as shown in diagram I1) via a secondary pathway stimulated by CAP/Cbl complex. CAP is an adapter protein containing a sorbin peptide like domain on the N-terminus and three SH3 domains on the C-terminus. The pathway begins with the phosphorylation of Cbl whereby the proline rich sequence of Cbl associates with the SH3 domain of CAP. On the other hand then SoHo domain of CAP interacts with flotillin protein. This interaction helps mediate the translocation of Cbl-CAP complex onto the lipid raft. Another adapter protein Crk2 interacts via its SH2 domain with the phosphorylated Cbl. Crk2 forms a connection with C3G protein which in turn interacts with TC10, a G-protein. This interaction causes GTP to convert to GDP which activates TC10. An activated TC10 protein signals GLUT4 vesicles to migrate to plasma membrane.  
Source of Insulin
The organ which is known to produce Insulin is the pancreas which forms a part of both the digestive and endocrine system in humans. The pancreas is mainly an exocrine gland, however, 2% of the total mass consist of the endocrine portion which is composed of islet of Langerhans. Within the Islets, the cells more specifically known as beta cells is known to produce insulin. 
An insufficient amount of Insulin has been a cause of many diseases, including Diabetes Mellitus type 1. A large number of patients with this type of condition lack the ability to produce adequate amount of Insulin and would rely on an external source of insulin. The use of Insulin sourced from a pig's pancreas was a common way of acquiring a source of external insulin, but more modern pharmaceuticals have provided with insulin produced from recombinant gene technology. Patients which use an external source of insulin is advised to inject the treatment subcutaneously to enable a longer lasting effect. 
The cell detects the level of insulin when the insulin receptors in the membrane is activated. The activation of these receptors lead on to a cascade which control glucose uptake by controlling the number of transport proteins.A certain type of transport protein known as GLUT 4 allow glucose from the blood to enter the cell. The migration of GLUT 4 proteins depends on the presence, or its absence/low level of insulin which will prevent the intake of glucose by the cells.
Metabolic actions of Insulin
The metabolic actions of insulin is transduced through the binding of cell surface receptor, tyrosine phosphorylation of IRS-1, activation of PI3-Kinase and phosphorylation of B/Akt protein kinase, not only mediates glucose uptake but it also plays an important role in the protective and adaptive responses to physiological stresses, such as thermal injury and sepsis. This results in a decrease of tissue injury and dysfunction. 
During normal function, the insulin signaling pathway regulate carbohydrate and adipose metabolism in the body. After a meal, the blood glucose levels rise, and this increase is detected by the Beta Cells in the pancreas which begins to secrete the stored insulin into the bloodstream. The endocrine organ attempts to stabilize the blood glucose levels through the release of insulin which act as a signal for the cells in the body to take up the glucose from the bloodstream. The tissue in the body respond to the hormone (insulin) by migrating Glut 4 molecule to the membrane which then function to provide active transport for glucose molecules to enter the cell. How glucose enter the cell Organs such as the liver, muscle and adipose are good examples of tissue which respond to the insulin peptide, and actively participate in maintaining a stable blood glucose level. 
Another property of Insulin is that it inhibit the release of glucagon which is a hormone that promotes the conversion of glycogen to glucose. When a subject's blood glucose level is low, the pancreas (alpha cells) release the hormone glucagon in the attempt to incrase blood glucose levels. The presence of Insulin prevents the conversion of glycogen, and therefore minimises the effect of any glucagon already present in the blood stream. The hormone's secrete by the Islet of Langerhans, insulin and glucagon work in opposition to maintain the blood glucose levels. 
During a meal, blood glucose level increase due to the presence of glucose in the food we consume. The increase in blood glucose levels are detected by the Beta Cells (Pancreas) which begins to release Insulin into the bloodstream.
Adipose (fat), skeletal muscle, and liver tissue respond to higher levels of insulin by increasing glycogen synthesis, glucose uptake and fat synthesis. In other words, the insulin signaling pathway informs the different tissue to store away and conserve energy (glucose molecules) in the form of glycogen and adipose cells. As a result, the blood glucose levels fall down to a level which is no longer toxic for the cells.  
Diagram F1 depicts the hormones, molecules and the different tissue that is involved in lowering blood glucose levels in response to Insulin signaling.
During Fasting, blood glucose levels tend to fall as the body utilities available glucose as an energy source. As a response to low blood glucose levels, the alpha cells in the pancreas begin to secrete glucagon which is detected by the liver, which then begins to increase the breakdown of glycogen to glucose. In terms of blood glucose levels, glucagon have the opposite effect of insulin as it mobilizes the stored energy (glycogen and adipose tissue) into readily available glucose molecules for ATP production.  During low levels of blood glucose, glucagon opposes the action of the hormone insulin . The two hormones are released into the blood stream in a stabilizing attempt by the pancreas to control blood glucose levels at all times. 
Diagram F2 on the right depicts the attempt by fat, skeletal and liver tissue to raise blood glucose levels after a period of fasting.
The hormone Insulin travels in the blood stream as a dissolved substance, and is usually degraded by endocytosis of the insulin receptor complex and the function of an insulin degrading enzyme.. An endogenously produced insulin molecule have a half life of 4-6 minutes and is degraded in less than an hour. 
There are two main obstacles which prevent the normal Insulin signaling pathway. One major problem is the absence/reduced number of Beta Cells in the pancreas as a result of a person's immune system. This condition is often referred to as an autoimmune disease as the body recognize its Beta Cells as foreign, and as a result the immune system attempt to remove their presence. Another major obstacles include insulin resistance in cells. Associated with obesity and a poor lifestyle, a person may respond less to insulin, and force the Beta Cells in the pancreas to increase the production of insulin. This condition is often referred to as insulinemia, where blood insulin levels are very high. As cells continue to be insulin resistant, beta cells in the pancreas may eventually be exhausted, and cease to exist.
The most known examples of a dysfunctional dysfunctional insulin signaling pathway is Diabetes Mellitus. The pathological defects in diabetes consist of peripheral insulin resistance, defect in the functioning of beta cell secretion, and excessive hepatic glucose production.  Type 1 diabetes is a result of failure of producing insulin in the pancreas, and requires the injection of insulin. Type 1 diabetes can arise due to a number of reasons, most which are due to a problem with insulin signaling pathway. Type 2 diabetes is a result from insulin resistance where the cells does not respond to an increased blood glucose level. Animation on Diabetes
Other conditions that are associated with abnormal signalling pathway include
- Type 1 Diabetes Mellitus (IDDM)
- Type 2 Diabetes Mellitus
- Hyperlipidemia (Dyslipidemia)
- Defects in myocardial signalling
|Abnormalities||Description||Signs and symptoms|
|Type 1 Diabetes Mellitus|| One of the most common condition which arise as a result of an absent/dysfunctioning insulin signalling pathway is Diabetes Mellitus. Diabetes is the condition where there is excessive blood glucose level and it is due to the insulin activity in the body.
Type 1 diabetes is an autoimmune disease characterised by the T-Cell destruction to the host's pancreatic beta cells.  Type 1 Diabetes Mellitus is often referred to as Islet Autoimmunity (IA). As a result, patients with Type 1 Diabetes Mellitus does not produce insulin, and will depend on an external source of insulin to stay alive as there is not enough endogenous insulin for the body to signal the intake of glucose from the blood stream.
|Type 2 Diabetes Mellitus||Type 2 Diabetes occurs when the fat and muscle cells which normally respond to insulin by extracting sugar from blood becomes insulin resistant. It is also characterized by a progressive decline in Beta cell function. Dysfunction of Beta cell can result in blood sugar control failure as high blood glucose level creates glucotoxicity , which can further damage Beta cells. Type 2 Diabetes Mellitus differ from type 1 in that it is preventable, and is to a certain degree reversible. This condition occurs often as a result of lack of fitness, poor lifestyle and a high body mass index.
Two problems which are often associated in patients with Type 2 Diabetes Mellitus are:
Other metabolic abnormalities associated with Type II diabetes include; Hypertension, Central obesity and Dyslipidemia which contributes largely to the increase of cardiovascular morbidity and mortality rate.
| At first, patients with Type 2 Diabetes may have no symptoms for many years.
|Hypertension and Hyperinsulinemia||It is known that individuals with abnormal glucose and insulin metabolism tend to have a higher risk of hypertension, and it has been discovered that patients with untreated tend to have higher insulin concentrations, and in many cases are resistant to an external insulin source for glucose uptake .Research have shown that hyperinsulinemia, which is caused by insulin resistance, leads to increased levels of Insulin in blood circulation as pancreatic cells over expresses insulin. . Patients with the condition often suffer from hypertension as higher levels of insulin promote high blood pressure by increasing sodium re absorption and sympathetic nervous system activity .||There are usually no signs and symptoms for Hypertension and Hyperinsulinemia, unless it causes hypoglycemia. Hypertension can cause serious problems such as:
|Obesity||An association between Obesity and Insulin resistance has been recognized for some time now. The reason why people with obesity are in higher risk of diabetes is because of insulin resistance. In muscles, lipids are either stored as extramyocellular lipids (EMCL) o r intramyocellular lipids (IMCL). When lipids are not consumed or completely oxidized, they may form dangerous active metabolites which can inhibit insulin signalling. As overweight individuals can improve insulin sensitivity by exercising regularly, IMCL is thought to be the missing link between obesity and insulin resistance development. Furthermore, it has also been found that individuals with decreased IMCL levels have better glucose control. The risk of obesity continues to increase as body fat increases because of decreasing sensitivity of insulin signalling. As a result, cells fail to respond to insulin, resulting in high blood glucose levels.||Risk Factors associated with obesity includes:
|Hyperlipidemia||In association with Diabetes Mellitus Type 2 is the condition of Hyperlipidemia. The hyperlipidemia is related to the level of insulin resistance found in the cells which is associated with VLDL (very low density lipoprotein), which are larger in size than normal VLDL (often termed, bad cholesterol)
 . In addition, greater level of insulin resistance is associated with a greater level of VLDL, as opposed to a smaller concentration of HDL (Low Density lipoprotein - often termed good cholesterol) .
|There are usually no symptoms for Hyperlipidemia. Risk factors associated with high cholesterol level includes:
How to lower cholesterol levels?
|Defects in Myocardial Insulin Signaling||In a study that uses porcine model of diet-induced obesity, using cardiac muscle of insulin resistant rodents, PI 3 Kinase activity and phosphorylation of Akt were found weakened. Along with these abnormalities, there was also an increase in serine phosphorylation of IRS-1. The increase in serine phosphorylation of IRS-1 reduces the effect insulin has on tyrosine phosphorylation of IRS-1. This in turn, effects the interaction of IRS-1 with Pi 3 Kinase.  In addition to this impairment of interaction between IRS-1 and PI 3 Kinase and Akt signalling, is the increased expression of the regulatory subunit of Pi 3 Kinase (p85).  An excessive amount of p85 means a competition between the p85 monomer and the PI3-Kinase for the IRS-1 binding sites, which can reduce the effect insulin-stimulated activation on the PI3-Kinase enzyme. ||There are usually no symptoms for Defects in Myocardial Insulin Signaling.
Risk Factors associated with obesity includes:
The number of people diagnosed with diseases associated with an abnormal Insulin signaling pathway is continually increasing worldwide. People diagnosed with Diabetes Mellitus alone are estimated to surpass half a billion people by 2030  and similar numbers are familiar in other insulin related diseases. A great amount of research is being carried on regulating levels of insulin, activation of GLUT 4 cells, and alternative method of transporting glucose into the cell. Below are a number of current research project which aim to minimise the effect of abnormal insulin signalling pathway and insulin resistance.
The Mediterranean Research Centre
A dysfunctioning signalling pathway of Insulin have often been associated with obesity. Diabetes Mellitus type 2 has been recognised to derive from lifestyle choices and a large number of patients with this condition are suffering from obesity. Obesity is described to be an excess growth of adipose tissue whcich eventually forms hypoxic areas within tissue. The Mediterranean Research Centre for Molecular Medicine, Nice, France have been studying the effect on hypoxia on the insulin signalling pathway in adipocyte and have come to the conclusion that hypoxia produces a state of insulin resistance. Their current research is to identify how to overcome the effect of hypoxia on the insullin signalling pathway. Their aim has been to identify the specific signalling molecules which are affected by hypoxia, and attempt to minimise the effect it has on the insulin signalling pathway of insulin. 
The Human Performance Laboratory
The Human Performance Laboratory consists of numerous researchers undertaking different investigations funded by NIH. Below are just 2 of the researchers who are currently working on respective projects.
The current projects that are being funded by NIH (National Institutes of Health) consist of "Physical Activity During Surgery-Induced Weight Loss" - which investigates into whether body composition and insulin action can be improved in gastric-bypass patients that have been exposed to additional endurance-oriented exercise. This project is performed by Joseph A. Houmard - Director of The Human Performance Laboratory, in collaboration with the University of Pittsburgh (continues into 2013). Clinical Trials outline
P. Darrell Neufer, Director of East Carolina Diabetes and Obesity Institute is also currently working on 2 projects:
- Mitochondria bioenergetics and etiology of insulin resistance
- Linking mitochondrial bioenergetics to insulin sensitivity
Hong Kong Diabetes Registry
The World Journal of Diabetes recently published an article exploring the links between diabetes, and the risk associated with insulin usage on cancer. The findings of Hong Kong Diabetes Registry concluded that although there are no evidence showing a relationship between insulin usage and an increased risk of cancer. However, they did suggest that the dysregulation in AMP-activated protein kinase pathway may have a significant part in the increasing the risk of cancer with patients that have diabetes. 
Glossary & Abbreviation
AKT is also known as Protein Kinase B or PKB is serine-threonine specific PK. Important as a messenger in glucose metabolism and plays a role in tumour cells
Alpha Cells Endocrine cells in the Pancreas located in the Islets of Langerhan that synthesise Glucagon.
Beta Cells Endocrine cells in the Pancreas located in the Islets of Langerhan that synthesise Insulin
CAP Protein fragment coded by c-Cbl gene, important for signalling
Cbl Human gene sequence coding for important cell signalling genes
Dyslipidemia refers to high blood cholesterol levels
GLUT4 Glucose transporter 4 that helps in translocation of glucose in the cell as response to insulin signalling
GSK3 Glycogen synthase kinase 3 - another serine-threonine kinase regulating the enzyme glycogen synthase that converts glucose into glycogen
HDL High Density Lipoprotein - also known as"good cholesterol"; unit of fat and proteins that carry cholesterol to the liver
Hyperglycemia High blood Glucose
IA Islet autoimmunity - where body's own immune system attacks the pancreatic produced Beta Cells
IDDM Insulin-Dependent Diabetes Mellitus (previous name for Type I Diabetes
Insulin Resistance inability to respond to and use the produced insulin to break down glucose for energy
IR Insulin Receptor - outer part of the cell that allows insulin binding, which then extracts glucose from blood to produce energy
IRS Insulin Receptor Substrates - adaptor proteins
IRS-1 Insulin receptor 1
Islet of Langerhans Special marked region within the pancreas containing special endocrine alpha, beta, delta, and PP cells.
LDL Low Density Lipoprotein - also known as "bad cholesterol"; high levels of LDL causes build up of cholesterol in the arteries
PI3 Kinase Phosphotidylinositol 3-Kinase - group of enzymes involved in cellular growth, proliferation, motility, differentiation, etc which are also involved in cancer tumors
Ptd(3,4,5)P3 Phsophatidylinositol (3,4,5) bisphosphate
PtdIns(4,5)P2 Phsophatidylinositol (4,5) bisphosphate - acts as a substrate for signalling proteins
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