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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

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Chapter 6 cell cell communication l.jpg

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


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_____________ 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 ______________)


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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


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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”


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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 l.jpg

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


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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


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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 ____________


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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


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C. JAK-STAT pathway- also a simpler pathway

Fig. 6.21


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D. Wnt signaling

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


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Apoptosis

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


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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


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Apoptosis is required for normal development

Elegans

Mammals

Fig. 6.28

Apaf-1 knock-out

Wild-type

Fig. 6.27


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  • 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


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Monitoring Apoptosis by ______________

Hoechst


Slide17 l.jpg

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 l.jpg

Monitoring Apoptosis by _________

1000X

M38

400X

Fg14

1000X

Hoechst

TUNEL


An example of signaling l.jpg

An example of __________ signaling

_________ signaling

Cell 1

Delta (Ligand)

Notch (receptor)

Cell 2


Another example of signaling l.jpg

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 l.jpg

Integrins interact with both extracellular and intracellular scaffolds

Fibronectin

Integrin

Actin


Another form of communication transmission of signals through l.jpg

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 l.jpg

  • 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 l.jpg

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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