8ackground

Complex unlcellular organlsms exlsLed on LarLh for approxlmaLely 23

bllllon years before Lhe flrsL mulLlcellular organlsms appeared
1hls long perlod for mulLlcellularlLy Lo evolve may be relaLed Lo
dlfflculLles developlng Lhe elaboraLe communlcaLlon machlnery
necessary for a mulLlcellular organlsm
Cells ln a mulLlcellular organlsm need Lo be able Lo produce slgnals Lo
communlcaLe and respond Lo slgnals from oLher cells ln Lhe
organlsm
1hese slgnals musL govern Lhelr own behavlor fot tbe beoeflt of tbe
otqoolsm os o wbole
commun|cat|onru|rart
Slgnal molecules an exLracellular slgnal molecule ls
produced by one cell and ls capable of Lravellng Lo
nelghborlng cells or Lo cells LhaL may be far away
2 8ecepLor proLelns Lhe cells ln an organlsm musL have
cell surface recepLor proLelns LhaL blnd Lo Lhe slgnal
molecule and communlcaLe lLs presence lnward lnLo Lhe
cell
3 lnLracellular slgnallng proLelns Lhese dlsLrlbuLe Lhe slgnal
Lo Lhe approprlaLe parLs of Lhe cell
4 1argeL proLelns Lhese are alLered when a slgnallng
paLhway ls acLlve and changes Lhe behavlor of Lhe cell
1he slgnal molecule blnds Lo Lhe
recepLor proLeln (whlch ls generally
locaLed ln Lhe plasma membrane)
2 1he recepLor acLlvaLes lnLracellular
slgnallng proLelns LhaL lnlLlaLe a
slgnallng cascade (a serles of
lnLracellular slgnallng molecules LhaL
acL sequenLlally)
3 1hls slgnallng cascade lnfluences a
LargeL proLeln alLerlng Lhls LargeL
proLeln and Lhus alLerlng Lhe
behavlor of Lhe cell
4 1hls process ls ofLen called slgnal
LransducLlon
llgure 3 ,olecolot 8loloqy of tbe cell ( Carland Sclence 2008)
A Simple Signaling Pathway
lLhough yeasL (unlcellular eukaryoLes) llve
lndependenLly" Lhey can lnfluence Lhe
behavlor of oLher yeasL
MaLlng facLor occbotomyces cetevlsloe
(buddlng yeasL) secreLe Lhe maLlng facLor
pepLlde LhaL slgnals yeasL of opposlLe
maLlng Lypes Lo sLop prollferaLlng and
prepare Lo maLe
1hese Lwo cells (haplold) can Lhen fuse Lo
form a dlplold cell whlch can Lhen undergo
melosls and sporulaLe generaLlng new
haplold cells
normal
8esponse Lo
maLlng facLor
llg 32 3
Lh
Ld
Signal Transduction in Unicellular
Organisms
8ecepLors 1ypes
Cell surface recepLors mosL slgnal molecules
cannoL cross Lhe plasma membrane and
Lherefore musL blnd Lo recepLors ln Lhe cell
surface
lnLracellular recepLors Some small slgnal
molecules can dlffuse across Lhe M and blnd Lo
recepLors locaLed ln Lhe cyLosol or nucleus
1hese slgnal molecules are generally
hydrophoblc and requlre carrler proLelns Lo be
LransporLed ln aqueous soluLlons (such as Lhe
bloodsLream)
nlmal cells communlcaLe by uslng hundreds of
klnds of slgnal molecules such as proLelns
small pepLldes amlno aclds sLerolds and even
gasses and lons
1hese slgnal molecules (called llgands ln
relaLlon Lo Lhelr recepLor) are ofLen presenL ln
very low concenLraLlons (Lyplcally 0
8
M)
llg 33 3
Lh
Ld
1ypes of cell communlcaLlon
ConLacLdependenL Lhe slgnal molecule remalns bound Lo Lhe cell LhaL produced lL and
Lherefore wlll only lnfluence cells LhaL dlrecLly conLacL lL1hls very local Lype of slgnallng ls very
lmporLanL ln Lhe developmenL of mulLlcellular organlsms and ln Lhe lmmune sysLem
2 aracrlne a slgnallng cell" produces a slgnal molecule LhaL ls secreLed buL only dlffuses a shorL
dlsLance 1hls slgnal molecule acLs as a local medlaLor LhaL affecLs cells only ln Lhe lmmedlaLe
envlronmenL of Lhe slgnallng cell 8ecause paracrlne slgnal molecules acL locally Lhelr dlffuslon
ls llmlLed lacLors LhaL llmlL Lhelr dlffuslon are rapld upLake by nelghborlng LargeL cells
desLrucLlon by exLracellular enzymes or by lmmoblllzaLlon ln Lhe exLracellular maLrlx
3
Lh
LdlLlon
1ypes of cell communlcaLlon
3 SynapLlc speclallzed cells called neurons make long processes (axons) LhaL conLacL cells far away
When a neuron ls sLlmulaLed lL sends an elecLrlcal lmpulse (acLlon poLenLlal) along Lhls axon Lo
Lhe LargeL cell 1hls lmpulse once lL reaches Lhe end of Lhe axon promoLes Lhe release of
chemlcal slgnals called neuroLransmlLLers 1hese dlffuse a very shorL dlsLance Lo Lhe LargeL cell
and acLlvaLe recepLors on lL
4 Lndocrlne an endocrlne cell secreLes a slgnal molecule called a hormone LhaL enLers Lhe
bloodsLream and ls dlsLrlbuLed wldely LhroughouL Lhe organlsm Lndocrlne slgnals can effecL any
cell LhaL expresses Lhe recepLor Lo Lhe released hormone
3
Lh
LdlLlon
uLocrlne slgnallng
When a cell sends a slgnal Lo an ldenLlcal cell Lype lncludlng Lhemselves
1hls ls common durlng developmenLal processes
uLocrlne slgnallng ls mosL effecLlve when lL occurs from a group of ldenLlcal cells slmulLaneously
1he concenLraLlon of Lhe auLocrlne slgnal accumulaLes Lhereby acLlvaLlng recepLors on Lhese same
cells uLocrlne slgnallng ls used Lo encourage groups of cells Lo make Lhe same developmenLal
declslons
LxLracellular Slgnallng 8esponse 1lmes
Slgnal responses such as lncreased growLh and cell dlvlslon
LhaL lnvolve changes ln gene expresslon and synLhesls of new proLelns
occur slowly (eg hrs) whlle Lhose LhaL lnvolve changes ln cell movemenL
secreLlon or meLabollsm occur rapldly (secs Lo mlns) SynapLlc responses
medlaLed by changes ln membrane poLenLlal occur ln mllllseconds
llgure 36 ,olecolot 8loloqy of tbe cell Carland Sclence 2008
Cenomic
reprogramming
One signal molecule can have several effects
1he neuroLransmlLLer aceLylchollne for example has dlfferenL effecLs on dlfferenL Lypes of
cells 1hls ls because
Cell Lypes respond Lo llgand blndlng of Lhe same recepLor dlfferenLly 1hese dlfferenL cells
may have dlfferenL Lypes of lnLracellular slgnallng proLelns for example
2 ulfferenL cells may express dlfferenL Lypes of recepLors LhaL blnd Lhe same llgand 1here are
dlfferenL Lypes of aceLylchollne recepLors for example
3
Lh
Ld
The Three Largest Classes of Cell Surface Receptors
lonchannelllnked recepLors 1hese recepLors are lnvolved ln rapld slgnallng evenLs mosL generally
found ln neurons 1he slgnal molecule (such as a neuroLransmlLLer) causes Lhese recepLors Lo
elLher open or close Lhereby allowlng or sLopplng Lhe movemenL of lons Lhrough lLs channel
1hls rapldly changes Lhe exclLablllLy of Lhe LargeL cell lonchannelllnked recepLors consLlLuLe a
large famlly of mulLlpass Lransmembrane proLelns
2 CproLelnllnked recepLors 1hese are recepLors LhaL upon llgand blndlng acLlvaLe a Lrlmerlc C1
blndlng proLeln (C proLeln) 1he acLlvaLed C proLeln Lhen affecLs oLher lnLracellular slgnallng
proLelns or LargeL proLelns dlrecLly ll CproLelnllnked recepLors are 7pass Lransmembrane
proLelns LhaL are a huge famlly of homologous molecules

8
lberLs llg 36 3Lh Ld
The Three Largest Classes of Cell Surface Receptors
3 Lnzymellnked recepLors Lhese recepLors are elLher enzymes Lhemselves or are dlrecLly assoclaLed
wlLh Lhe enzymes LhaL Lhey acLlvaLe 1hese are slnglepass Lransmembrane recepLors wlLh Lhe
enzymaLlc porLlon of Lhe recepLor belng lnLracellular 1he ma[orlLy of enzymellned recepLors are
proLeln klnases or assoclaLe wlLh proLeln klnases
llg 36 3
Lh
Ld
(
sL
messenger)
2
nd
messenger
Second messengers Small molecules LhaL are
produced ln large numbers as a consequence of
recepLor acLlvaLlon 1hese molecules dlffuse readlly
away from Lhelr source Cycllc nucleoLldes and
dlacylglycerol are examples llrsL messengers are Lhe
slgnal lLself
8elay proLelns pass Lhe slgnal on Lo Lhe nexL
lnLracellular slgnallng proLeln
dapLor proLelns llnk one slgnallng proLeln Lo anoLher
buL do noL convey Lhe slgnal Lhemselves CrlLlcal for
Lhe formaLlon of slgnallng complexes
Scaffold proLelns proLelns LhaL blnd mulLlple slgnallng
proLelns LogeLher ln a funcLlonal complex and ofLen
hold Lhem ln a speclflc locaLlon
mpllfler proLelns ampllfy Lhe slgnal ofLen by
generaLlng second messengers (lon channels and
enzymes)
nchorlng proLelns locaLe slgnallng proLelns ln a
preclse locaLlon ln Lhe cell by LeLherlng Lhem Lo Lhe
membrane or cyLoskeleLon
Cene regulaLory proLelns Lhese are acLlvaLed aL Lhe
cell surface by recepLors and LranslocaLe lnLo Lhe
nucleus Lo regulaLe gene expresslon
llg 37 3
Lh
Ld
ntracellular Signaling Networks
Molecular switches: many intracellular proteins act as switches in which they are
converted from an inactive to active state, and can be converted back.
roLeln phosphorylaLlon hosphorylaLlon of Lhe molecular swlLch (by a proLeln klnase)
causes Lhe converslon beLween acLlve and lnacLlve sLaLes CfLen proLeln klnases
Lhemselves are molecular swlLches uephosphorylaLlon (by proLeln phosphaLases)
converLs Lhe molecular swlLch back Lo lLs sLarLlng polnL MosL klnases are
serlne/Lhreonlne klnases wlLh a smaller class phosphorylaLlng Lyroslne resldues (Lyroslne
klnases)
2 C1blndlng proLelns SwlLch from lnacLlve Lo acLlve upon blndlng of C1 Cnce Lhese are
acLlvaLed Lhey have lnLrlnslc C1ase acLlvlLy LhaL wlll evenLually hydrolyze Lhelr C1 Lo
Cu Lhus converLlng Lhem back Lo an lnacLlve form
lberLs llg 38 3
Lh
Ld
Signal ntegration
Cells ofLen requlre mulLlple slgnal proLelns colncldenLally Lo Lrlgger a response CfLen
mulLlple slgnals requlre lnLegraLor proLelns whlch requlre more Lhan one lnpuL slgnal Lo
generaLe an ouLpuL slgnal LhaL propagaLes a downsLream slgnallng cascade
Examples:
() slngle proLeln requlres phosphorylaLlon on Lwo dlfferenL resldues by Lwo lndependenL
slgnallng paLhways Lo be acLlvaLed (proLelns such as ? are ofLen called colncldence deLecLors)
(8) 1wo proLelns upon phosphorylaLlon by Lwo dlfferenL slgnallng cascades assoclaLe LogeLher Lo
form an acLlve lnLracellular slgnallng molecule
llg 320 3
Lh
Ld
ntracellular Reception
E
x
t
r
a
c
e
l
l
u
l
a
r

R
e
c
e
p
t
i
o
n
e.g., insulin
e.g., epinephrine
G

P
r
o
t
e
i
n
-
L
i
n
k
e
d

R
e
c
e
p
t
o
r
s
note how activation is
reversible
the more ligand
binding, the greater
the cellular response
on-Channel Receptors
S
i
g
n
a
l

A
m
p
l
i
f
i
c
a
t
i
o
n

(
C
a
s
c
a
d
e
)
Note how, via catalysis, one ligand molecule binding gives rise to many
new intracellullar molecules
Phosphorylation Cascade
E
p
i
n
e
p
h
r
i
n
e

G
l
y
c
o
g
e
n

B
r
e
a
k
d
o
w
n
Hormone (epinephrine or glucagon)
via G Protein (G
-
-GTP)
Adenylate cyclase Adenylate cyclase
(inactive) (active)
catalysis

ATP cyclic AMP PP
i

Activation Phosphodiesterase
AMP
Protein kinase A Protein kinase A
(inactive) (active)
ATP
ADP
Phosphorylase kinase Phosphorylase kinase (P)
(b-inactive) (a-active)
Phosphatase ATP
P
i
ADP

Phosphorylase Phosphorylase (P)
(b-allosteric) (a-active)
Phosphatase
P
i

10
0
molecules
10
2
molecules
10
4
molecules
10
4
molecules
10
5
molecules
10
6
molecules
10
8
mol Glu-1-Phosphate
Second Messengers
Cyclic AMP (cAMP) 2
nd
Messenger
nositol Triphosphate 2
nd
Messenger