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Chapter 6- Cell-cell communication. More definitions. \_\_\_\_\_\_\_\_\_ - 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. Fig. 6.2.

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chapter 6 cell cell communication
Chapter 6- Cell-cell communication

More definitions

_________-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

Fig. 6.2

Example- Pax6 is required for optic vesicle to respond to an inducer, but Pax6 is not the inducer

Lacking nose and eyes

Hence, Pax6 makes cells _____________

Pax6 null

Wild-type

slide2
_____________ interaction-Tissue A requires tissue B to respond in a certain way (analogy to a book _______________)
  • Instructive vs permissive interactions

____________ 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 ______________)

slide3
Epithelial-mesenchymal interactions

Fig. 6.7

  • __________- sheets of cells from any germ layer
  • ____________- unconnected cells (from mesoderm or neural crest)
  • All organs have both of these cell types

Mesen-

chyme

Wing

epithelium

Wing

_______

specificity

Thigh

Epithelial-mesenchymal interactions

Foot

________

specificity

Thus, mesenchyme __________ epithelium

slide4
Epithelial-mesenchymal interactions

Newt with tadpole suckers

Regional specificity

Epithelial-mesenchymal interactions

_______

specificity

Frog gastrula

Newt gastrula

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

Newt gastrula

Frog gastrula

Frog with newt “balancers”

paracrine factors
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
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
slide7
Cell surface receptor pathways

BLA512 1/5/98 update

Smad

Smad

Smad

Smad

STAT

STAT

STAT

STAT

Elk-1

NFkB

CREB

Gene

Fos

Fos

jun

jun

AP1

AP1

P

P

Enzyme-linked

Ion channel-linked

No details shown

G-protein-linked

PDGF, EGF, IFa,b,and g,

IL-2 ,IL-3, IL-4, IL-6

TNFa

TGF-b

PLCg

Grb2

Jak

G proteins

TRADD

Gs

Golf

FADD

Gq

Go

GNRPs

(e.g. Sos)

TRAF

Complexity!

Ca++ from ER

Ras

IP3

PIP

Adenylyl cyclase

Cytoplasm

Raf

(a MAPKKK)

PLCb

DAG

MEKK

(a MAPKKK)

NIK

AMP

cAMP

MAPKK

(e.g.MEK)

PKC

JNKK

IKK

PKA

Caspases

JNK

IkB/NFkB

IkB/NFkB

MAP-kinase (ERK)

Cell death

Elk-1

jun

JNK

Gene

Gene

Nucleus

Gene

Gene

signal transduction pathways
Signal transduction pathways

Phosphorylation is key

General pathway

Fig. 6.14

A. Receptor tyrosine kinase (RTK)

  • ________ binds receptor
  • Receptor undergoes _______
  • Receptor ____________ occurs
  • Receptor __________________
  • Receptor binds _____________
  • Adaptor protein binds ________
  • G-protein recruits ____
  • Raf phophorylates ____
  • ____ phosphorylates ERK
  • ERK phosphoryates a
    • ____________________
  • Transcription is ____________
slide9
B. TGF-b signalling- a simpler pathway
  • Ligand binds _______
  • Two _______ receptors dimerize
  • _____________________occurs
  • Receptor phosphorylates ________
  • SMADs ___________
  • SMADs enter _________and bind ____
  • Transcription is _____________

Fig. 6.20

slide11
D. Wnt signaling

If mutate B-catenin, constitutive activation of myc gene– Tumor formation

slide12
Apoptosis

Jacobson et al., Cell 88:347 (1997)

slide13
Fas-null mice

Lymph

nodes

Spleen

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
slide14
Apoptosis is required for normal development

Elegans

Mammals

Fig. 6.28

Apaf-1 knock-out

Wild-type

Fig. 6.27

slide15
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)

Receptor-mediated Apoptosis

Caspases-3, -6 and -7

Protective

slide17
0h

0h

3h

3h

Monitoring Apoptosis by _______________

Fg-14

1000 bp ladder

M38

100 bp ladder

7h

7h

5 kb

2 kb

1 kb

0.5kb

slide18
Monitoring Apoptosis by _________

1000X

M38

400X

Fg14

1000X

Hoechst

TUNEL

an example of signaling
An example of __________ signaling

_________ signaling

Cell 1

Delta (Ligand)

Notch (receptor)

Cell 2

another example of signaling
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

slide21
Integrins interact with both extracellular and intracellular scaffolds

Fibronectin

Integrin

Actin

another form of communication transmission of signals through
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 _______________
slide23
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

slide24
LPB

LPS

FasL

TNF

CD14

TNFR

TLR-4

FasR

FADD

IL1R1

TRADD

FADD

Caspase 8

Caspase 8

TAK1

RIP

TGFBR

TRAF2

P38 MAPK

MyD88

Sorb.

P38 MAPK

NIK

TRAF6

IRAK

TNF

TPL-2

MEKK1, 2, 3

PKC

EGFR

JNKK

IKK

MEK

Calyculin A,

Okadaic Acid

JNK

PD098059

p65

ERK1,2

PDTC

c-jun

ALLN, HMA

p105

Apoptosis

IkB

NF-kB

Proteasome

SN50

P105 phos, degraded

NF-kB-responsive genes

ROS

A1, A20, ,Fas, FasL,TNF, Bcl2,

TRAF1,2, c-IAP1,2

LPS-mediated apoptosis: Which pathway is defective?

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