Chapter 6- Cell-cell 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

More definitions

Pax6 nullWild-type

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

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 ______________)

• __________- sheets of cells from any germ layer

• ____________- unconnected cells (from mesoderm or neural crest)

• All organs have both of these cell types

Epithelial-mesenchymal interactions

Epithelial-mesenchymal interactions

_______specificity

________specificity

Wing

Foot

Thigh

Mesen-chyme

Wing epithelium

Thus, mesenchyme __________ epithelium

Fig. 6.7

Epithelial-mesenchymal interactions

Epithelial-mesenchymal interactions

Regional specificity

_______specificity

Frog gastrula

Newt gastrula

Newt gastrula

Frog gastrula

Thus, mesenchyme dictates _______ type, but epithelium dictates ____ of the organ

Newt with tadpole suckers

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

Fibroblast growth factor (FGF) – binds FGF receptors (FGFRs)These are receptor tyrosine kinases

Example of _________ signaling

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

Ion channel-linked No details shown

G-protein-linked Enzyme-linked

GqGo

G proteins

PKC

GsGolf

PKA

CREB

Gene

P

Adenylyl cyclase

cAMPAMP

PIP

DAG

IP3Ca++ from ER

MAP-kinase (ERK)

Ras

Raf (a MAPKKK)

MAPKK(e.g.MEK)

NFkB

Gene

IkB/NFkB

Elk-1

Gene

P

Grb2

GNRPs (e.g. Sos)

Jak

Gene

TGF-PDGF, EGF, IF,and IL-2 ,IL-3, IL-4, IL-6

GeneNucleus

Cytop

lasm

Elk-1 junJNK

Fos junAP1

Fos junAP1

Cell surface receptor pathwaysBLA512 1/5/98 update

JNK

MEKK(a MAPKKK)

JNKK

TNF

TRADDFADDTRAF

Cell deathIkB/NFkB

PLC

STAT

NIK

IKK

Smad

STAT

STATSTAT

Smad

SmadSmad

PLC

Caspases

Signal transduction pathwaysPhosphorylation is key

A. Receptor tyrosine kinase (RTK)

1. ________ binds receptor2. Receptor undergoes _______3. Receptor ____________ occurs4. Receptor __________________5. Receptor binds _____________6. Adaptor protein binds ________7. G-protein recruits ____8. Raf phophorylates ____9. ____ phosphorylates ERK10. ERK phosphoryates a

____________________ 11. Transcription is ____________

Fig. 6.14General pathway

B. TGF- signalling- a simpler pathway

Fig. 6.20

1. Ligand binds _______2. Two _______ receptors

dimerize3. _____________________

occurs4. Receptor phosphorylates

________5. SMADs ___________6. SMADs enter

_________and bind ____7. Transcription is

_____________

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 little- ___________• Splenomegaly• Lymphadenopathy• Cholangiocarcinoma• Hepatocellular Carcinoma

Too much- ________________ disease• Alcohol-induced liver disease• Autoimmune disease• Primary biliarry cirrhosis• Wilson’s disease• Ischemia reperfusion injury• Virus hepatitis

Fas-null mice

SpleenLymph nodes

Fig. 6.28

Apaf-1 knock-outWild-type

Elegans Mammals

Apoptosis is required for normal development

Fig. 6.27

Receptor-mediated Apoptosis

Caspases-3, -6 and -7

Protective

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)

Hoechst

Monitoring Apoptosis by ______________

100

bp

lad

der

1000

bp

lad

der

0h 3h7h0h 3h 7h

Fg-14M38

1 kb

0.5kb

2 kb

Monitoring Apoptosis by _______________

5 kb

Hoechst TUNEL

1000X

400X

1000X

M38

Fg14

Monitoring Apoptosis by _________

An example of __________ signaling_________ signaling

Cell 1

Cell 2

Delta (Ligand)

Notch (receptor)

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

Integrin

Fibronectin

Actin

Integrins interact with both extracellular and intracellular scaffolds

Another form of communication- _______transmission of signals through

__________________

•Does not requires a __________, only regulation of small molecules through a port•Ports are composed of _______________

Fig. 6.38

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

CD14

LPS LPB

TLR-4

LPS-mediated apoptosis: Which pathway is defective?

NF-B

NF-kB-responsive genes

NIK

IKK

PDTC

IkB

ProteasomeSN50

A1, A20, ,Fas, FasL,TNF, Bcl2,TRAF1,2, c-IAP1,2

IL1R1

MyD88IRAK

TAK1

TRAF6MEKK1, 2, 3 PKC

p105

p65

TPL-2

ROS

FADD

Caspase 8

ALLN, HMA

Apoptosis

P38 MAPK

Calyculin A,Okadaic Acid

Sorb.P38 MAPK

JNKK

JNK

c-jun

P105 phos, degraded

FasR

FasL

FADD

Caspase 8

TNFTNFR

TRADD

RIP TRAF2 TGFBR

TNFEGFR

MEK

ERK1,2PD098059