receptor mech 3 Flashcards
list the enzyme linked receptors
Tyrosine receptors kinase
Insulin
Epidermal growth factor (EGF) or
Platelet derived growth factor (PDGF)
JAK/STAT
Growth Hormone
Interferon
Serine Threonine receptor kinase
TGFβlist the nuclear receptors
Glucocorticoid
Thyroid hormone
how many transmembrane domains do enzyme linked receptors have
Predominantly single transmembrane domain receptors
what are enzyme linked receptors involved in the regulation of ?
Involved in the regulation of : cell growth, division, differentiation, survival, migration.
how does phosphorylation form docking domains>
• The way this is achieved is that the proteins which binds to the activated receptor recognises a specifc sequence of amino acids that include a phosphorylated tyrosine.
- Binding of an agonist to a kinase receptor leads first to dimerisation and then auto phosphorylation of specific residues.
• Dimerisation brings together two receptor molecules allowing auto-phosphorylation of specific tyrosine residues
• Not all tyrosine residues are can be phosphorylated, only specific tyrosine residues.
• The phospho-tyrosine together with surrounding amino acids form a motif which us recognised by other proteins within a transduction pathway through SH2 domains of other proteins allowing them to bind and undergo activation
what are tyrosine kinase linked domains
- Tyrosine kinase linked receptor : activated tyrosine kinase receptor have phosphprylated tyrosines . The phosphorylated tyrosines are specific phosphrylated tyrosines and form docking sites for other proteins in the signal transduction cascade.
describe the activation of tyrosine kinase recpetors
• Grb-2 binds to the tyrosine through its SH2 domain. Grb-2 will undergo a conformational change which will then allow it to interact with another protein called GEF through a different receptor domain called the SH3 domain. This will also cause a conformational change in the GEF which will allow it to interact with and activate RAS.
• Ras is a membrane associated protein which in the inactive state is bound to GDP. Upon activation the GDP will be expelled and exchanged for GTP.
• The RAS GTP is activated and can activate a number of intracellular pathways.
• In addition to the activation of Ras, there is also the activation of other proteins such as PI3 kinase. This will interact and recognise specific tyrosine residues in the activated tyrosine kinase receptor.
• This kinase will phoshorylate a membrane associated lipid called PIP2. This will then form PIP3.
• PIP3 will bind to and activate 2 proteins: PDK1 and PKB.
Pdk1 will then phosphorylate and activate pkb which will then disscoiate and phosphorylate and activate other proteins in the singal transduction cascade.
what is grb2
adaptor protein
describe the insulin receptor
· Targetting kinase receptors but structurall different and consist of 2 alpha chains and 2 beta chains held together by disulphide links.
· In the absence of insulin, the receptor is in a comformation that does not allow the phosphorylation of the receptor to take place.
· However, binding of insulin to the receptor causes a conformational change bringing together the 2 beta subunits, and this allows autophosphorylation to take place.
· The autophosphorylation, similar to other rceptor targeting kinases, will recruit other proteins to the receptor.
· It will recruit insulin receptor substrate (IRS) . This is via the SH2 domain.
· Recruitment to the receptor causes confromational change in activation and allows for the recruimtment of other singal transduction proteins, including PI3 kinase. PI3 kinase results in the phophorylation of PIP2 forming PIP3.
· PIP3 will then recruit 2 proteins, PDK1 and PKB. PDK1 will activate the PBK which will then dissociate.
· The tissues that are responsive to insulin, can lead to a number of psiological responses: the liver and muscle - increase in glycogen synthesis and can also lead to stimulation of protein synthesis.
· The activation of PKB can also stimulate the expression of glucose transporters in the cell surface of some cells. This will increase glucose uptake.
The insulin receptor also recruits other proteins such as RAS and phospholipase C which leads to the synthesis of IP3 which mobilises calcium and DAG which can activate protien kinase c.
what is a superfamily
Consist of a ligand binding domain and protein tyrosine kinase domain
what does phosphotyrosine interact with
- Phosphotyrosine interacts with proteins that contain SH2 domains
how can tyrosine kinase linked receptors be inactivated
- As activation of these receptors leads to phosphorylation, de-phosphorylation leads to inactivation.
- Phosphatases are activated as a result of the receptor activation. This means that the receptor will initiate its own inactivation. There are other phosphatases that are present within the cell which are responsivle for the inactivation of these signalling pathways. Example : PTEN which will remove the phosphates or inhibit the phosphorylation of the molecules turning the singal off.
Therefore the signalling process sets in motion events that leads to signal termination
describe the inactivation of RAS
· The inactive Ras has bound gdp , and upon activation the gdp is replaced by gtp.
· In the active form, the recruitment of other singalling proteins can occur, forming an active complex.
· How is this regulated ?
· In addition to the other responses of the Ras protien, It also has GTPase activity. This removes the phosphate and will inactivate the RAS.
· The kinetics of this is very slow, so in order to enhance this, the RAS protein will interact with GAP, GTPase activating protein, which is a protien that will bind to activated Ras and stimulated GTPase activation within the protien.
This will lead to the dissociation of the GTP and the falling apart of the Ras complex, which leads to the recycling of the activated RAS back to the inactive conformation, for further stimulation.
DESCRIBE mutations in key regulatory mechanism
· A process that can be altered is the receptor expression. In some diseases there is increased receptor expression
· In other diseases there is loss of phosphatase activity, removal of this activity can lead to increased pdk1 activation.
· Other mutations can result in the loss of GTPase activity, which results in the RASgtp being activated for longer periods of time.
There can also be loss of phosphatase activity that remove phosphates from the receptor itself, inhibiting the inactivation process.
how can tyrosine kinase activation be reversed
- Tyrosine kinase activation can be reversed in a number of ways :
- Removal of receptors from the self surface, internalisation and stimulation of phsphatases which remove the phosphataces from the receptor.
• Removal of phosphates from the receptor by the action of phosphatases
PTEN is a phosphatase that dephosphorylates PIP3
