RTKs

Question 1

Structure function of adaptor proteins

Answer 1

-SH2 domains bind to phosphorylated tyrosine residues -SH3 domains bind to proline rich motifs in intracellular proteins

Question 2

Examples

Answer 2

NGF acts on TRK to which neurones respond

HGF/SF acts on Met to which EPITHELIAL CELLS respond

SCF acts onKIT to which HEMATOPOIETIC, MESENCHYMAL CELLS RESPOND

EGF acts on EGFR to which EPITHELIAL CELLS, some MESENCHYMAL CELLS RESPOND

Question 3

Activation

Answer 3

• Typically exist as a monomer
• Ligand binding stabilizes the receptor as a binder structure resulting in cross-phosohorylation of multiple intracellular tyrosine residues

Question 4

Possible outcomes of mutation

Answer 4

• Truncation and constitutive activation
• elevated cell surface expression
• autocrine signalling (?)

Question 5

EGF signalling outcomes (2 main pathways)

Answer 5

Question 6

Paracrine signalling

Answer 6

PDGF from epithelial cells interacts with stromal cells while TGF from stromal cell interacts with epithelial cells regulating survival/proliferation

cancer…

Question 7

Mechanisms of signalling initiation

Answer 7

• Phosphorylated tyrosine sites act as attatchment points for:
  1. Scaffold proteins e.g. GRB2, SHC, NCK, CRK OR DOK-R
  2. Effector proteins may bind i.e. PLCgama, Kinases such as SRC or Abl or RASgap
  3. Effectors can phosphphorylate different sites on the receptor promoting the attachment of other effectors/adaptors

Question 8

Structure of adaptors/ effectors

Answer 8

Question 9

SH2 domain and SH3 domain

Answer 9

SH2 domain binds to phosphorylated tyrosine residues

SH3 domain binds to proline rich areas of effector proteins

Question 10

MAPK signal cascade

Answer 10

N-terminal of the SH3 domain of GRB associates with proline rich areas of SOS which then catalyses GTP/GDP exchange at membrane bounr RAS resuting in its activation

Question 11

Ras active/inactive cycle

Answer 11

Question 12

PI3K and PIP3

Answer 12

• Can be activated by Ras or binding via a P85 scaffold protein
• Phosphorylates the 3- hydroxyl of PIP2 forming PIP3
• PIP3 draws proteins with Pleckstrin homology to the membrane to the membrane, such as Akt and Rho-GEFS
• PTEN is a phosphatase which keeps PIP3 levels very low in the absence of Akt (Oncogene)

Question 13

outcomes of PI3K signalling

Answer 13

-Akt activation results in