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Flashcards in Tyrosine Kinases Deck (72)
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What is the similar molecular architecture of all RTKs

A ligand binding region in the extracellular domain, a single transmembrane helix, and a cytoplasmic region that contains the protein tyrosine kinase domain plus additional carboxy terminal and juxtamembrane regulatory regions.


Which amino acids are capable of being phosphorylated and why?

Serine, Threonine and tyrosine - because they have a free hydroxyl group allowing transfer of the phosphate.


What is the role of EGF

Stimulates proliferation of various cell types


What is the role of the insulin receptor

Stimulates carbohydrate utilisation and protein synthesis


What is the role of the IGF receptor

Cell growth and survival


What is the role of Trk A receptor

NGF binds, stimulating survival and growth of some neurons


What is the role of the VEGF receptor

Angiogenesis - therefore receptor antagonists are a good target for cancer treatment.


What role does FGF have and what is the result of knocking it out in mice

Wound healing impaired in knockout mice. In vitro scratching of cells - healing takes longer in the FGF knockout cells.


How does nerve growth factor bind Trk A

It is a dimer and cross-links two TrkA molecules without any direct contact between the two receptors


How does stem cell factor bing KIT

Also cross-links between two KIT molecules, but also two Ig-like domains D4 and D5 which reorientate and interact upon ligand binding. Kit therefore combines ligand mediated as well as receptor mediated dimerization.


How does FGF bind to FGFR

Bind to one part of the receptor and induces a conformational change in the extracellular domain to increase its affinity for the neighbouring receptor/domain - The ligands dont interact


How does EGF bind ErbB/ EGFR

Dimerisation of ErbB is mediated entirely by the receptor. Binding simultaneously to two sites (DI and DIII) within the same receptor molecule. This causes a conformational change allowing for two extracellular domains to bind.


What is the general structure of the intracellular kinase domains

All TKDs have a small N lobe and a C lobe. Key regulatory elements such as the activation loop and the alphaC helix in the N lobe adopt a specific configuration in activated TKDs which is required for catalysis of phosphotransfer.


What is the structure of the insulin receptor

Exists as a pre-assembled receptor dimer composed of four subunits held together by disulphide bridges. However they are too far apart to cross-phosphorylate


What happens to the insulin receptor upon insulin binding

conformational change so cross-phosphorylation can occur because the tyrosine kinases are now close enough.


What is TKD cis-
autoinhibition by the activation loop and which receptors exhibit it

Insulin and FGF receptors: The activation loop of the receptor projects into the active site of its own kinase domain blocking access of both ATP and protein substrates.


How is cis autoinhibition relieved and what is the consequence of this

Insulin binding causes a key tyrosine (Y1162) on the activation loop in one TKD within the dimer to become phosphorylated by its partner. This trans-phosphorylation disrupts the cis-autoinhibitory interactions, the phosphorylated activation loop flips out of the molecule into the active state, freeing the ATP binding site and allowing for phosphorylation of downstream signalling proteins. (IRS)


What is juxtamembrane autoinhibition

sequences in the juxtamembrane region make extensive contacts with several parts of the TKD, including the activation loop, and stabilize and autoinhibitory conformation, where the C lobe is flipped back and blocks the binding site.


what is the result of disrupted juxtamembrane autoinhibition

Mutations in the juxtamembrane domain result in a constitutively active RTKs in KIT/PDGFR families. Frequently resulting in cancer.


Is there an activation loop present on the EGFR



What is the result of EGF binding on the TKDs

Extracellular dimerisation means TKDs come into close contact and there is an allosteric effect between the two domains., it is an asymmetric dimer.


What is the activator receiver model of EGFR activation

The C-lobe of one TKD (the activator) makes intimate contact with the N-lobe of the second TKD (the receiver). These contacts induce a conformational change in the N-lobe of the receiver kinase that disrupt cis-autoinhibitory interactions seen in the monomer.


What is an important characteristic of EGFRs as a result of the receiver activator model.

The receiver kinase can adopt the active configuration without activation loop phosphorylation.


How are EGFR/ErbR compromised in cancers.

Oncogenic mutations causing disruption to cis-autoinhibitory interactions means that the receptor can be activated without the need for ligand binding.


What is the role of the phosphorylation sites not found at the activation loop and cytoplasmic domain.

Act as docking sites for cytosolic downstream signalling molecules which become translocated to the plasma membrane.


What is the result of C terminal tail phosphorylation of the EGFR

Acts an anchor for downstream signalling molecules


What is an SH2 domain

Found on signalling proteins, the SH2 domain is capable of recognising and binding to phosphorylated tyrosine residues


What is an SH3 domain

A domain capable of binding proline rich regions


What part of the SH2 domain is responsible for binding

The phosphate group makes a tight bond with arginine found on the SH2 domain.


What is GRB2

Signalling molecule formed of one SH2 and two SH3 domains.