O survivaI depends on an eIaborate

interceIIuIar communication network that

coordinates growth, differentiation and
metaboIism
O ceIIs adjacent to one another frequentIy
communicate through ceII-ceII contact
O other forms of communication cover
Iarger distances = extraceIIuIar signaIing
moIecuIes

ommunication between ceIIs requires:

Iigand: the signaIing moIecuIe
receptor protein: the moIecuIe to which
the receptor binds
may be on the pIasma membrane or
within the ceII

%here are four basic mechanisms for

ceIIuIar communication:
1. Direct contact
2. Paracrine signaIing
3. Endocrine signaIing
4. Synaptic signaIing

Direct contact -
moIecuIes on the
surface of one ceII
are recognized by
receptors on the
adjacent ceII

Paracrine signaIing
- signaI reIeased
from a ceII has an
effect on
neighboring ceIIs

Endocrine signaIing
- hormones
reIeased from a
ceII affect other
ceIIs throughout
the body

Synaptic signaIing -
nerve ceIIs reIease
the signaI
(neurotransmitter)
which binds to
receptors on
nearby ceIIs
O (1) synthesis of the signaIing moIecuIe by the signaIing ceII
O (2) reIease of the signaIing moIecuIe by the signaIing ceII
O (3) transport of the signaI to the target ceII
O (4) detection of the signaI by a specific receptor protein -
receptor-Iigand specificity
O (5) a change in ceIIuIar metaboIism, function, or deveIopment
= ceIIuIar response - triggered by the receptor-Iigand
compIex - specific to the Iigand-receptor compIex
O (6) removaI of the signaI, which usuaIIy terminates the
ceIIuIar response - degredation of Iigand
1. Long Distance ommunication: Hormones
O SignaI hemicaIs
O Made in endocrine
ceIIs
O %ransported via
bIood
O Receptors on target
ceIIs
Figure 6-2a: Long distance cell-to-cell communication
Note how specificity is determined by receptor protein
Note dependence on Systemic CircuIation (bIood/Iymph)
2. Short Distance ommunication:
Paracrines and Autocrines
O LocaI communication
O SignaI chemicaIs
diffuse to target
O ExampIe: ytokines
O Autocrine-receptor on
same ceII
O Paracrine-neighboring
ceIIs
Figure 6-1c: Direct and local cell-to-cell communication
e.g., Histamine reIeased from damaged ceIIs in infIammation
e.g., Interferon reIease by viraI-infected ceIIs
ote both absence of and Iack-of-dependence on Systemic ircuIation
- many compounds can act through two or even
three types of ceII signaIing
e.g. - growth factors (e.g. EGF) - paracrine
and autocrine and endocrine
- epinephrine - endocrine and
paracrine
1. Reception of extraceIIuIar signaI by ceII
2. %ransduction of signaI from outside of ceII to
inside of ceII-often muIti-stepped
ote not necessariIy transduction of Iigand
3. eIIuIar Response
Response is inititiated and/or occurs entireIy
within receiving ceII
O SignaI moIecuIe (Iigand)
O Receptor
O IntraceIIuIar signaI
O %arget protein
O Response
Figure 6-3: Signal pathways
2a. %ransduction
2b. %ransduction
2c. %ransduction
2d. %ransduction
1. Reception
3. Response
Responses usuaIIy invoIve increasing or decreasing some Protein's Function
2a. %ransduction
2b. %ransduction
1. Reception
3. Response
Note that more than one
response can resuIt from the
reception of a singIe Iigand
ytosoIic or ucIear
LipophiIic Iigand enters
ceII
Often activates gene
SIower response
eII membrane
Lipophobic Iigand can't
enter ceII
Outer surface receptor
Fast response
Figure 6-4: Target cell receptors
e.g., steroid hormones
e.g., nitric oxide
e.g., insulin
e.g., epinephrine
OLigand- gated channeI
OReceptor enzymes
OG-protein-coupIed
OIntegrin
Figure 6-5: Four classes of membrane receptors
SmaII signaI produces
Iarge ceII response
AmpIification enzyme
ascade
Figure 6-7: Signal amplification
ote how, ;ia cataIysis, one ligand molecule binding
gives rise to many new intraceIIuIIar moIecuIes
Figure 6-14: Summary of signal transduction systems
Otwo types
OIipid soIubIe
Owater soIubIe
- Iipid-soIubIe hormones can easiIy
enter a ceII by diffusing through the
pIasma membrane
- PROBLEM: how do they traveI in the
water-based bIood??
- SOLU%IO: they are carried by
carrier-proteins
- these hormones then enter their
target ceII where they resuIt in a
specific ceIIuIar effect or response
- water soIubIe hormones can easiIy traveI within the bIood
- PROBLEM: how do they enter a ceII and resuIt in a ceIIuIar response??
- SOLU%IO: binding to specific ceII-surface receptors
- this binding activates the receptor and resuIts in a series of ceIIuIar events caIIed
the second messenger system
O Steroids
O Iipids derived from choIesteroI in
SER
O different functionaI groups attached
to core of structure provide
uniqueness
O interact with specific intraceIIuIar
receptors (within the ceII) to turn
specific genes on or off
O effective for hours or days
O %hyroid hormones
O tyrosine ring pIus attached iodines
are Iipid-soIubIe
O activate enzymes invoIved in the
cataboIism of fats and gIucose
O heIp set our basaI metaboIic rate
O Retinoids
O vitamin A derivatives
O have dramatic effects on
proIiferation and differentiation pIus
ceIIuIar death (i.e. apoptosis)
O Amino acid derivatives, smaII
peptides and protein hormones
O modified amino acids or amino
acids put together
O serotonin, meIatonin,
histamine, epinephrine
O Iarger peptide hormones
O insuIin and gIucagon
O Eicosanoids
O derived from arachidonic acid
(fatty acid)
O prostagIandins or Ieukotrienes
O prostagIandins despite being
IipidphiIic - bind to ceII surface
receptors
O Hormone diffuses through
phosphoIipid biIayer &
into ceII
O Binds to receptor turning
on/off specific genes
O ew mRA is formed &
directs synthesis of new
proteins
O ew protein aIters ceII's
activity
O an not diffuse through
pIasma membrane
O Hormone receptors are
integraI membrane proteins
O act as first messenger
O Receptor protein activates G-
protein in membrane
O G-protein activates adenyIate
cycIase to convert A%P to
cAMP in the cytosoI
ycIic AMP is the 2nd
messenger
Activates kinases in the
cytosoI to speed up/sIow
down physioIogicaI
responses
Phosphodiesterase
inactivates cAMP quickIy
eII response is turned off
unIess new hormone
moIecuIes arrive
ertain smaII moIecuIes and ions are key components of signaIing
pathways (second messengers).
%he extra ceIIuIar signaI moIecuIe that binds to the membrane receptor is
a pathway's "first messenger".
Because second messengers are both smaII and water-
soIubIe, they can readiIy spread throughout the ceII by diffusion.
%he two most wideIy used second messengers are cycIic AMP and
caIcium ions, a2+.
A Iarge variety of reIay proteins are sensitive to the
cytosoIic concentration of one or the other of these
second messengers.
ycIic AMP (cAMP).
is a component of many G-protein-signaIing pathways.
%he signaI moIecuIe - the "first messanger" - activates a G-
protein-Iinked receptor, which activates a specific G protein. In turn,
the G protein activates adenyIyI cycIase, which cataIyzes the
conversion of A%P to cAMP.
Second Messengers

1'
3'
5'
4'
2'
cAMP
- a key event in the evoIution of muIticeIIuIarity is the abiIity for ceIIs
to adhere to one another and be abIe to communicate with each
other
- evoIved a series of ceII-adhesion moIecuIes or AMs that aIIow
interaction with each other and with the surrounding extraceIIuIar
matrix (EM)
-this resuIts in coordinated functioning of tissues
-HOW??
- these interactions resuIt in the activation of specific signaI transduction
cascades eventuaIIy resuIting in the desired ceIIuIar effect
- therefore the physicaI interaction of AMs with the EM can turn
pathways
on or off - ceIIuIar effect
e.g. ceIIuIar interactions with the adhesion protein b1-integrin can
resuIt in activation of the MAPK cascade
1. cadherins - ceII-ceII adhesion
-caIcium dependent
e.g, E-cadherin, P-cadherin
2. Ig superfamiIy of AMs - ceII-ceII
adhesion
e.g. -AM, V-AM
-caIcium-independent
-some are found enriched on
specific ceII types - -AM
3. Integrins - major ceII-matrix
adhesion moIecuIe
e.g. a1 integrin, b1 integrin
-cadherins are a famiIy of caIcium-dependent AMs
-major moIecuIes of ceII-ceII adhesion (homophiIic)
-over 40 different are known
e.g. E or epitheIiaI cadherin
or neuraI cadherin
-tissues have speciaIized junctions made of cadherins
1. adherens junction
- continuous band of cadherins found in epitheIiaI
ceIIs
- connects ceIIs tightIy and interact with the
actin portion of the cytoskeIeton
2. Desmosomes
- aIso found in high in epitheIiaI tissues
-ceIIs attach via cadherins - connect to protein
"pIaques" that attach to the pIasma
membrane and to intermediate fiIaments
within the cytoskeIeton
almost all cells have specialized junctions that allow the free
passage of materials
(e.g. signaling molecules) back and forth
these junctions = gap junctions
made of a channel protein called connexon
connexons interact to form channels between two cells
one important compound small enough to traverse this junction is
the second messenger cAM!
also allows passage of calcium ions and other ions crucial to
signaling
(sodium, phosphate)
these gaps are not freeswinging gates
they actually open and close in response to ion
concentrations
thereby restricting the flow of too many ions
they also exclude materials based on size
%he distance invoIved in junctions can aIso
be used to cIassify the types of
communication possibIe.
1. Autocrine (same ceII).
2. Synaptic (one ceII immediateIy in
contact).
3. %ethered (one ceII in immediate
contact, but non-mobiIe Iigand).
4. Paracrine (nearby ceII,
community coherence,
neuromoduIation).
5. Endocrine (hormonaI, action-at-
a-distance).
6. PheromonaI (different organism).
!rotein AT! !rotein !

AD!
!
i

Protein Kinase




Protein Phosphatase
ote steps involved:
1. Ligand Reception
. Receptor Dimerization
3. atalysis (!hosphorylization)
4. Subsequent !rotein Activation
5. Further Transduction
6. Response
!rotein AT! !rotein !

AD!
!
i

Protein Kinase




Protein Phosphatase
This reversibility contributes to the dynamic nature of
cells:
A protein that is activated by a !rotein Kinase in turn
is inactivated by a !rotein !hosphatase
This means that the effect of signals can't last
1470;07
For the cellular response to continue, more signal
must be received
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

molecules
10
4
molecules
10
4
molecules
10
5
molecules
10
6
molecules
10
8
mol Glu1!hosphate
1. ote how same ligand gives rise to different
responses
. ells differ in terms of their proteins
3. Different proteins respond differently to the same
environental signals
4. (note, though, same receptors, different relay)
5. Different cells behave differently because some,
but not all proteins can differ between cell types