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Tyrosine kinases. http://msbl.helsinki.fi/tkseminar. Biological responses. Activation of Gene expression. Signal trans- duction. Signaling molecules. Producer cell. RNA. Receptor binding. Target cell. proliferation, differentiation, migration, metabolism, etc.

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Tyrosine kinases

Tyrosine kinases

http://msbl.helsinki.fi/tkseminar


Biological responses
Biological responses

Activation of

Gene expression

Signal

trans-

duction

Signaling molecules

Producer

cell

RNA

Receptor binding

Target

cell

proliferation, differentiation, migration, metabolism, etc.



Receptor tyrosine kinases
Receptor Tyrosine Kinases

NH2

ligand binding

extracellular

transmembrane

juxtamembrane

ATP

tyrosine kinase

substrate

binding

carboxy-terminal tail

COOH


Vegf x vegf r1

VEGF xVEGF-R1


Rtk subclasses
RTK subclasses

I

II

III

IV

ss

ss

ss

ss

EGF-R

IGF-1-R

VEGF-R3

FGF-R

PDGF-Ra



Rtk ligands
RTK ligands

  • Cytokines (EGF, FGF, CSF-1, insulin)

  • Membrane-bound proteins (ephrins)

  • Extracellular matrix components (HSPGs)

  • Some RTKs need two ligands for activation



Dimerization or oligomerization
Dimerization or oligomerization

  • Bivalent ligand

  • (e.g. VEGF, PDGF)

  • Ligand-induced conformational change (probably EGF)

  • Intracomplex conformational change (e.g. insulin)


Transmembrane signal transfer
Transmembrane signal transfer

  • Exact mechanism unknown

  • Same or similar mechanism for all RTKs (evidence from hybrid receptors)


Autophosphorylation
Autophosphorylation

  • Specific Tyr residues, usually outside the

  • tyrosine kinase domain (juxtamembrane domain, cytoplasmic tail, kinase insert)

  • Purposes:

  • - Regulation of tyrosine kinase activity

  • - Recruitment of signaling molecules


Signaling proteins are modular molecules
Signaling proteins are modular molecules

SH2

PTB

SH3

PH/FYVE

PZB

WW

  • SH2 (Src-homolgy 2)

  • PTB (phosphotyrosine binding)

  • SH3 (Src-homolgy 3)

  • PH (pleckstrin homology)/FYVE

  • PDZ

  • WW


Sh2 src homology 2 ptb phosphotyrosine binding
SH2 (Src-homology 2)/PTB (phosphotyrosine binding)

  • Bind to PY (and sometimes Y)

  • Specificity is achieved through the context

  • SH2: 1-6 amino acids C-terminal to PY

  • PTB: 3-5 amino aids N-terminal to PY (or Y)


Sh3 ww
SH3 & WW

SH3 (Src-homology 3)

  • Binds to proline motif PXXP

WW

  • Binds to proline motif PXPX


Ph fyve pdz
PH/FYVE/PDZ

PH (pleckstrin homology)/FYVE

  • PH domain binds to phosphoinositides (membrane- localization)

  • FYVE domain binds specifically PtdIns-3-P

PDZ (PSD-95, DDLP, ZP1)

  • Bind to hydrophobic C-terminal strtches of target proteins


Assembly of a specific signaling complex
Assembly of a specific signaling complex

membrane

P

PTB

Enzymatic

activity

PH/FYVE

SH3

WW

PDZ

SH2

Kinases

Phosphatases

PLC-g

Ras-GAP

Rho-GRF

P

Cellular Targets


Docking proteins
Docking proteins

Indirect recruitment is the main recruitment method

for some receptors (insulin receptor, FGF receptors)

Membrane

localization

Receptor

binding

Tyrosines

Myristyl.

PTB

FRS2a,b

P

P

P

P

P

Dos

PH

P

P

P

P

P

P

P

TM

LAT

P

P

P

P

P


Topics in activation of effector proteins
Topics in activation of effector proteins

  • Activation by Membrane Translocation

  • Activation by a Conformational Change

  • Activation by Tyrosine Phosphorylation


Activation of signaling molecules pdgf receptor
Activation of signaling molecules: PDGF receptor

1. Membrane translocation

2. Conformational

Change

3. Tyrosine Phosphorylation




3 steps to activation
3 Steps to activation

  • Ligand-induced oligomerization orconformational change

  • Autophosphorylation/crossphosphorylation

  • Recruitment of signaling molecules tophosphorylated tyrosines (“signalingcomplexes”)

  • Termination of Signaling (endocytosis)





Dominant negative receptors vegfr 3 mutations in hereditary lymphedema
Dominant Negative Receptors:VEGFR-3 mutations in hereditary lymphedema

ss

S641P

P1114L

VEGF-R3


Further reading
Further reading

Schlessinger, J. (2000): Cell Signaling by Receptor Tyrosine Kinases.

Cell, Vol. 103, 211-225.


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