Vorlesung: Molekulare Mechanismen der Signaltransduktion
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Vorlesung: Molekulare Mechanismen der Signaltransduktion
Lehrbuch der Molekularen Zellbiologie, m. CD-ROM von Bruce Alberts, Dennis Bray, Karen Hopkin
Molecular Cell Biology von Harvey Lodish, Arnold Berk, Paul Matsudaira
908 Seiten - Wiley-VCH Erscheinungsdatum: April 2005 ISBN: 3527311602 Preis: EUR 69,00
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General Principles in Signal Transduction Signals
Receptors
Mediator(s)
Effector(s)
Response
-Kinases -Phospholipases -GTPases -Adaptors -Transcription Factors -Structural Proteins -Enzymes -Proliferation -Differentiation -Apoptosis -Cell activation
General Principles in Signal Transduction
General Principles in Signal Transduction
General Principles in Signal Transduction
General Principles in Signal Transduction
General Principles in Signal Transduction
General Principles in Signal Transduction
General Principles in Signal Transduction Signals
Receptors
Hydrophobic Signals
Hydrophilic Signals
Mediator(s) Intracellular Receptors
Response
General Principles in Signal Transduction
Steroid Receptor Family • Cytoplasmic transcription factors • Bind lipophilic ligands – Estrogen, progesterone, testosterone – Vitamin D Steroid sex hormones – Glucocorticoids and mineralocorticoids – Thyroid hormone (nuclear receptor)
Steroid Receptor Signaling
Steroid Receptor Signaling
Steroid Receptor Structure
General Principles in Signal Transduction
General Principles in Signal Transduction A
B
D
C
Different classes of cell surface receptors
O. Modlich 29.11.
J. Bode 8./15.11.
nächste Woche
W. Schulz 20.12.
Two main apoptosis signaling pathways F. Essmann (22.11.) Death ligand
Death receptor FADD
cytokines
Bad
TCR
Bim
p53
Puma Noxa
Pro-Caspase-8 Bcl-2 Bcl-xLL
Bid Caspase-8 (active)
Bax Bak mitochondrium Caspase-9
Omi/HtrA2
AIF
Smac/Diablo
Cyt c
Apaf-1
IAP
cytoplasm
Caspase-3 (executioner caspases)
DFF/CAD
Death Substrates
Caspase-independent Death DNA Fragmentation
nucleus
General Principles in Signal Transduction Signals Hydrophilic Signals Receptors
Mediator(s)
Response
General Principles in Signal Transduction
-Kinases -Phospholipases -Second messengers -GTPases -Adaptors
Biochemical Reactions in Signal Transduction Kinases
-protein kinases phosphorylate their substrates -phosphorylation changes the activity, subcellular location, or aggregation of the proteins
Biochemical Reactions in Signal Transduction Kinases Nucleophiler Angriff
Energiegefälle: Kein Rückreaktion !
Biochemical Reactions in Signal Transduction Kinases Primary structure of a kinase Kinase domain ( approx. 30 kDa) Subdomains
I
II
III
IV
V
AXK
VI
VII
VIII
IX
X
XI
Activation loop (T-loop)
Tyr Kinases: Src, EGF-R, PDGF-R, JAK Ser/Thr Kinases: PKC, Raf, MAPK, Akt Dual-specificity kinases: MEK, MKK Lipid Kinase: PI3K
General Principles in Signal Transduction
-Kinases -Phospholipases -Second messengers -GTPases -Adaptors
Biochemical Reactions in Signal Transduction Phospholipases
-phospholipase C (PLC) catabolizes phospholipids (PIP2) generating IP3 -IP3 binds a receptor and increases cytosolic calcium -increased cytosolic calcium activates other signaling mechanisms
General Principles in Signal Transduction
-Kinases -Phospholipases -Second messengers -GTPases -Adaptors
Second Messengers • Cyclic nucleotides – Cyclic AMP and cyclic GMP
• Lipid metabolites – Diacylglycerol – Inositol triphosphate
• Calcium
Calcium Calcium concentrations extracellular: 1-2 mM cytosolic: 50 - 100 nM intracellular lumenal (ER etc.): 30 - 300 µM
transient calcium influx into the cytosol
Clinical Application: Immunosuppression by FK506 and Cyclosporin A
(Calcium-Sensor)
(Phosphatase)
(Transkriptionsfaktor)
Genexpression
General Principles in Signal Transduction
-Kinases -Phospholipases -Second messengers -GTPases -Adaptors
General Principles in Signal Transduction GTP-binding proteins in signal transduction
a) G-Proteins (heterotrimeric GTPases)
29.11.
b) monomeric GTPases = small GTPases = ras-like GTPases
Biochemical Reactions in Signal Transduction GTPases
GEFs
GAPs Signal -G proteins are turned “on” and “off” by GTP and GDP, respectively - active G proteins transmit the signal to other “downstream” proteins
Biochemical Reactions in Signal Transduction GTPases GTPases: Ras, Rac1, Rho, Cdc42 GEFs: Sos, Ras-GRP, Vav1
Vav1
General Principles in Signal Transduction
-Kinases -Phospholipases -Second messengers -GTPases -Adaptors
Biochemical Reactions in Signal Transduction Adaptor proteins
Example: SH2 domains -recognize phosphoryated tyrosines -Recruit signaling proteins to receptor
-adaptors have no enzymatic activity of their own -function is to recruit signaling enzymes to the receptor-ligand complex -this concentrates signaling proteins and increases efficiency
Biochemical Reactions in Signal Transduction SH2 Adaptor Proteins • • •
Example: SH2 domains -recognize phosphoryated tyrosines -Recruit signaling proteins to receptor
Many proteins have a domain called SH2 Portion that recognizes phosphotyrosine Interacts with phosphotyrosine (like a ligand and receptor)
xxxxxYxxxx
P xxxxxYxxxx
Biochemical Reactions in Signal Transduction Adaptor proteins Protein-protein interaction domains SH2
14-3-3
SH3
P -Y-X-X-hyPTB
-P-X-X-P-X-
R-S-X-S-X-P
WW
PH
P -hy-X-N-P-X-Y-
P
-P-P-X-Y-
PIP3
Biochemical Reactions in Signal Transduction Adaptor proteins Cytoplasmic adaptor proteins MW (kD)
Interaction partners
Expression
Grb2
28
Sos,LAT,c-Cbl,Shc,SLP-76, Vav,SHP-2,WASP,HPK1
ubiquitous
Grap
28
Sos,LAT,Shc,SAM68
B-Cells, T-Cells
Name
Structure
PxxP
Gads Nck-1
47 PxxP
Shb PxxP
Shc
PxxP
40
PxxP
SH2-Binding Site SH3-Binding Site
55,66 46,52,66
SH3-Domain
T-Cells, NK Cells Mast cells. Macrophages, Thrombocytes Sos,SLP-76,WASP,PAK,Cbl ubiquitous LAT,Shc,SLP-76,HPK1
Grb2,LAT,PI3K,Eps8, PLCγ1,CD3ζ,Src Grb2,SHIP,ZAP-70,CD3ζ, Igα/β,RasGAP
PTB-Domain
ubiquitous ubiquitous
SH2-Domain
Biochemical Reactions in Signal Transduction Adaptor proteins Transmembrane adaptor proteins Name
Structure
MW (kD)
Interaction partners
Expression
36-38
Grb2,Gads,SLP-76, PLCγ1/2,c-Cbl,PI3K
T-Cells, NK Cells, Mast cells, Platelets
75-85
Csk,Fyn
Ubiquitous
SIT
30-40
SHP2
B-Cells, T-Cells
TRIM
29-30
PI3K
T-Cells, NK Cells
LAT PAG/Cbp
PxxP
PxxP
TM
PxxP
SH2-Binding Site SH3-Binding Site
A. Leo and B.Schraven, Current Opinion in Immunology, 2001
Next week: Signaling from receptor tyrosine kinases
Stimulates Mitogen Activated Protein kinases (MAPK)
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