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25,000 genes

320 cell types

700 Liver-specific genes

Signal transduction-~4000 genes (16 % of

genome)

Receptors- 1540 (5%)

Kinases- 868 (2.8%)

Other components- 968 (3.2%)

Signaling molecules 376(1.2%)

Chapter 15- Cell CommunicationPart I- General signaling strategies

Part II- G protein signaling

Part III- Enzyme-linked cell surface receptors

Part IV- Proteolysis-dependent signaling pathways

Outline

A. Two cell types

Part I- General signaling strategies

B. A typical signaling pathwayC. Most signaling molecules are hydrophilic (water loving) D. Some signaling molecules are hydrophobic (water hating) E. A review of membranes (from chapter 10) F. Signaling over short or long distancesG. Autocrine signalingH. Cells respond to specific combinations of factorsI. Signaling through gap junctionsJ. Different cells respond differently to the same signal moleculesK. Nuclear receptors are ligand-activated gene regulatory proteins L. Three classes of cell-surface receptorsM. Common features of G protein-linked and enzyme-linked receptors

Chapter 15- Cell Communication

1. Signaling cell

A. Two cell types

Release •Proteins•___________•Amino acids•_____________•_____________•Dissolved gases (CO, NO)

2. Target cell

Most secreted by ___________ or

_________

These are termed ________

Respond by means of ___________

Part I- General signaling strategies

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

MAPKKK

MAPKKK

p38

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

B. A typical signaling pathway

Part I- General signaling strategies

C. Most signaling molecules are __________ (water loving)

Thus, cannot cross plasma membrane

D. Some signaling molecules are ______________ (water hating)

These may move easily through the plasma membrane

Part I- General signaling strategies

E. A review of membranes (from chapter 10)

1. A typical membrane- a __________________ with embedded __________________

Part I- General signaling strategies

________ head

____________ tail

2. A membrane phospholipid

Composed of fatty acids

E. A review of membranes (from chapter 10) Part I- General signaling strategies

3. Membranes are composed of four major _____________

Part I- General signaling strategies

F. Signaling over short or long distances

1. __________________ 2. _____________________

Requires _________ contact a. Paracrine- act locally

Fast-acting, _________, high concentration

Part I- General signaling strategies

2. Contact independent (continued)

b. ___________ c. _____________

Fast acting, ____________ Slow, _______________, low concentrations

e.g. hormones

Part I- General signaling strategies

G. __________ signaling

Cell secretes signal molecules that bind back to own _______

Function- _________ decisions made by a group of cells.

Part I- General signaling strategies

H. Signaling through ____________

•Small molecules are shared through these ports

•Ca++, cAMP can pass, but not proteins or nucleic acids

I. Cells respond to specific ____________ of factors

Part I- General signaling strategies

J. Different cells respond differently to the _______ signal molecules

Example- acetylcholine

Part I- General signaling strategies

K. Nuclear receptors are _______________ gene regulatory proteins

b. Examples of signaling molecules that bind _________ receptors

•____________________- derived from cholesterol; produced in adrenal, ovary, testis• ________________- increase cell metabolism• ______________ - from vitamin A; impt. in development• _________ (UV synthesizes); Regulates Ca++ metabolisma. All are small, _________molecules carried by _________proteins

1. Ligands include

Part I- General signaling strategies

K. Nuclear receptors are ligand-activated gene regulatory proteins

c. Nuclear Receptors- belong to ______________ receptor superfamily

d. All have three domains:

1. ____________________ domainInteracts with ____________

Part I- General signaling strategies

2. ___________________ domain

3. __________________ domain

e. Steroid hormones exhibit two response phases

1. _______ response

_________ response genes activated

K. Nuclear receptors are ligand-activated gene regulatory proteins

Part I- General signaling strategies

e. Steroid hormones exhibit two response phases

2. ________ secondary response

a. Primary response genes are ________ _______

b. Secondary response genes _______ _____

K. Nuclear receptors are ligand-activated gene regulatory proteins

Part I- General signaling strategies

L. Three classes of cell-surface receptors

1. _____________-linked - (Transmitter gated ion channel)

Example- ______________

2. __________-linked – Acts through a ________________________ _______________(G protein)

All are ______ transmembrane proteins

Part I- General signaling strategies

L. Three classes of cell-surface receptors

3. ___________-linked Includes __________________

Most are ____________ transmembrane proteins

Part I- General signaling strategies

M. Common features of G protein-linked and enzyme-linked receptors

1. Both become active via ________________2. Both use phosphorylation ______________3. Phosphorylation occurs at _______, _____or ________residues4. ___% of mammalian genes encode these enzymes 5. Many are “__________________”

M. Common features of G protein-linked and enzyme-linked receptors

6. These signaling complexes can either be on a ________________...

M. Common features of G protein-linked and enzyme-linked receptors

…. Or ________________once the receptor is activated.

7. Cells can respond ___________….

….or _________ to increasing signal molecules

Conc. of effector molecules

% m

ax. a

ctiv

atio

n % m

a x. a

ctiv

atio

n

M. Common features of G protein-linked and enzyme-linked receptors

The response remains after the signal disappears

Example- Muscle cell determination- Turn on muscle-specific genes that regulate their own expression

How? 1. The ________ activates the receptor

M. Common features of G protein-linked and enzyme-linked receptors

8. Cellular memory

2. Activate a ___________________

9. Cells can also become ______________ to the signal

How?•Ligand binding cause ____________ of receptor•Receptor ______________•______________ protein inactivated•______________ protein produced

Part I- General signaling strategies