Chapter 6- Cell-cell
More definitions communication
_________-interaction between two or more distinct cells or tissues
_________- the cell of tissue producing the signal
__________- the cell or tissue being induced
_________ the ability to respond to a given inducer
Example- Pax6 is
required for optic
vesicle to respond
to an inducer, but
Pax6 is not the
inducer
Hence, Pax6 makes
cells _____________
Fig. 6.2
Lacking
nose and
eyes
Wild-type
Pax6 null
1. Instructive vs permissive interactions
_____________ interaction-Tissue A requires tissue B
to respond in a certain way (analogy to a book
_______________)
____________ interaction-Tissue A does not require
tissue B to respond in a certain way, but only needs to
be in a certain environment (analogy to a book
______________)
Epithelial-mesenchymal interactions
• __________- sheets of cells from
any germ layer
• ____________- unconnected cells
(from mesoderm or neural crest) Mesenchyme
• All organs have both of these cell
types
Wing
_______
specificity
Thigh
Epithelialmesenchymal
Foot
interactions
________
specificity
Wing
epithelium
Fig. 6.7
Thus, mesenchyme __________
epithelium
Epithelial-mesenchymal interactions
Newt with
tadpole
suckers
Regional
specificity
Epithelialmesenchyma
l interactions
_______
specificity
Thus, mesenchyme dictates
_______ type, but epithelium
dictates ____ of the organ
Frog
gastrula
Newt
gastrula
Newt
gastrula
Frog
gastrula Frog
with newt
“balancers”
Paracrine factors
__________factors- diffusible molecules that can
travel small distances to signal a neighboring cell
__________signaling- cell-cell interactions by direct
contact
Example of _________ signaling
Fibroblast growth factor (FGF) – binds FGF receptors (FGFRs)
These are receptor tyrosine kinases
FGF (________)
FGFR
(______)
__________________
yields activation and
subsequent
phosphorylation of a
second protein
Other well-known paracrine
factors
• _________ family- (3 in vertebrates)-create
boundaries, induce development
• _____ family- (15 in vertebrates)- limb
polarity, muscle development
• _________ superfamily (>30 members)bone, kidney, neuronal , etc. differentiation
BLA512 1/5/98 update
Cell surface receptor pathways
Enzyme-linked
Ion channel-linked G-protein-linked
No details shown
PDGF, EGF, IFa,b,and g,
IL-2 ,IL-3, IL-4, IL-6
TNFa
TGF-b
PLCg
Grb2 Jak
G proteins
Gs
Golf
Gq
Go
Ca++ from ER
Ras
IP3
PLCb
AMP
GNRPs
(e.g. Sos)
PIP
Adenylyl cyclase
(a MAPKKK)
cAMP
PKC
Smad
JNKK
NIK
IKK
STAT
JNK
IkB/NFkB MAP-kinase (ERK)
Caspases
IkB/NFkB
Cell death
Elk-1
P
MEKK
(a MAPKKK)
MAPKK
(e.g.MEK)
PKA
TRADD
FADD
TRAF
STAT
Raf
DAG
Smad
jun
CREB
JNK
Gene
Fos
jun
AP1
NFkB
Gene
P
Elk-1
Nucleus
STAT
STAT
Fos
Gene
jun
AP1
Smad
Smad
Gene
Gene
Signal transduction pathways
Phosphorylation is key
A. Receptor tyrosine kinase (RTK)
1. ________ binds receptor
2. Receptor undergoes _______
3. Receptor ____________ occurs
4. Receptor __________________
5. Receptor binds _____________
6. Adaptor protein binds ________
7. G-protein recruits ____
8. Raf phophorylates ____
9. ____ phosphorylates ERK
10. ERK phosphoryates a
____________________
11. Transcription is ____________
General pathway Fig. 6.14
B. TGF-b signalling- a simpler pathway
1. Ligand binds _______
2. Two _______ receptors
dimerize
3. _____________________
occurs
4. Receptor phosphorylates
________
5. SMADs ___________
6. SMADs enter
_________and bind ____
7. Transcription is
_____________
Fig. 6.20
C. JAK-STAT pathway- also a simpler pathway
Fig. 6.21
D. Wnt signaling
If mutate B-catenin,
constitutive activation of myc
gene– Tumor formation
Apoptosis
Jacobson et al., Cell 88:347 (1997)
Too much and too little
Too much- ________________ disease
• Alcohol-induced liver disease
• Autoimmune disease
• Primary biliarry cirrhosis
• Wilson’s disease
• Ischemia reperfusion injury
• Virus hepatitis
Too little- ___________
• Splenomegaly
• Lymphadenopathy
• Cholangiocarcinoma
• Hepatocellular Carcinoma
Fas-null mice
Lymph
nodes
Spleen
Apoptosis is required for normal development
Elegans
Mammals
Fig. 6.28
Wild-type
Fig. 6.27
Apaf-1 knock-out
Receptor-mediated Apoptosis
Cleavage of Death substrates
•structural proteins (e.g. actin)
•kinases (e.g. MEKK, PKC)
•cell cycle proteins (pRb, PARP)
•DNA repair enzymes
•DNA nucleases
•Anti-apoptotic proteins (Bcl-2)
Caspases-3, -6 and -7
Protective
Monitoring Apoptosis by ______________
Hoechst
Monitoring Apoptosis by _______________
M38
Fg-14
0h 3h 7h 0h 3h 7h
5 kb
2 kb
1 kb
0.5kb
Monitoring Apoptosis by _________
1000X
M38
400X
Fg14
1000X
Hoechst
TUNEL
An example of __________ signaling
_________ signaling
Cell 1
Delta (Ligand)
Notch (receptor)
Cell 2
Another example of ____________
signaling
The ___________________
• The stuff between cells
• Affects cell adhesion,
_______________, epithelial sheet
formation
• Includes collagen, proteoglycans,
fibronectin and laminin
_______ are the _______________ for
extracellular matrix molecules
Integrins interact with both extracellular and intracellular scaffolds
Fibronectin
Integrin
Actin
Another form of communication_______transmission of signals through
__________________
Fig. 6.38
•Does not requires a
__________, only
regulation of small
molecules through a port
•Ports are composed of
_______________
Signaling pathways exhibit ____________A major challenge in biology- How to get specificity
from _______________pathways
Example: Two pathways
direct lymphocyte
development
Point of _________
Fig. 6.40
LPS-mediated apoptosis: Which pathway is defective?
LPB
LPS
FasL
TNF
TNFR
FasR
FADD
Caspase 8
Sorb.
CD14
RIP
TRAF2
JNKK
p65
p105
c-jun
FADD
Caspase 8
P38 MAPK
NIK
MEKK1, 2, 3
JNK
IL1R1
TRADD
P38 MAPK
TPL-2
TLR-4
Calyculin A,
Okadaic Acid
PDTC
TAK1
TRAF6
MyD88
IRAK
TNF
PKC
EGFR
IKK
MEK
PD098059
ERK1,2
ALLN, HMA
IkB
NF-kB
P105 phos, degraded
TGFBR
SN50
Apoptosis
Proteasome
NF-kB-responsive genes
A1, A20, ,Fas, FasL,TNF, Bcl2,
TRAF1,2, c-IAP1,2
ROS