cellular regulation son2.10.09

8/8/2019 Cellular Regulation Son2.10.09

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Prof.DrProf.Dr.Turgay.Turgay sbirsbir

CELLULAR REGULATIONCELLULAR REGULATION


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GrowthGrowth factorsfactors

GrowthGrowth factorsfactors areare proteinsproteins thatthatbindbind toto receptorsreceptors onon thethe cellcellsurfacesurface,, withwith thethe primaryprimary resultresult ofofactivatingactivating cellularcellular proliferationproliferation

andand//oror differentiondifferention.... ManyMany growthgrowth factorsfactors areare

stimulatingstimulating cellularcellular divisiondivision ininnumerousnumerous differentdifferent cellcell typestypes;; whilewhileothersothers specificspecific


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CellCell--surface receptorssurface receptors

CellCell--surface receptors aresurface receptors areproteins that bind factorsproteins that bind factorssuch as hormones or growthsuch as hormones or growth

factors, and transmit thefactors, and transmit theexternal signal inside the cell,external signal inside the cell,ultimately resulting inultimately resulting inprocesses such as cell growthprocesses such as cell growthand differentiation.and differentiation.


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These receptors reside on the cellThese receptors reside on the cellmembrane and typically consist ofmembrane and typically consist ofthree parts:three parts:

a sensing segment that sticksa sensing segment that sticks

outside the cell;outside the cell; a middle segment that runsa middle segment that runs

through the cell membrane;through the cell membrane;

and a segment that sticks insideand a segment that sticks insidethe cell and transmits the signalthe cell and transmits the signal

inside the cell.inside the cell.


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AmongAmong thethe majoritymajority ofof growthgrowth factorsfactors,,whichwhich stimulatestimulate proliferationproliferation,, therethere maymay

bebe somesome notednoted exceptionsexceptions.. ForFor exampleexample

BothBoth tumortumor necrosisnecrosis factorfactor --EE (TNF(TNF-- EE ))andand somesome formsforms ofof thethe tranformingtranforminggrowthgrowth factorfactor-- FF cancan inhibitinhibit thetheproliferationproliferation ofof somesome cellcell typestypes,, whilewhilestimulatingstimulating proliferationproliferation inin otherother cellscells..


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INNATE IMMUNITYINNATE IMMUNITYInnate immunity (also called natural or native immunity) consists of cellular

and biochemical defense mechanisms.These mechanisms react only to microbes and not to noninfectious substances,and they respond in essentially the same way to repeated infections.

Innate immunity consists of:Innate immunity consists of:

BarriersBarriers

((physicalphysical::skinskin,,hairhair,,mucousmucous))((chemicachemicall::sweatsweat,,tearstears,,salivasaliva,,

stomach acidstomach acid,, urineurine

Cellular responseCellular response phagocytosisphagocytosis

inflammatory reactioninflammatory reaction NK (natural killer) and mastNK (natural killer) and mast

cellscells

Soluble factorsSoluble factors


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Innate and Adaptive ImmunityInnate and Adaptive ImmunityThe principal componentsof innate immunity are;

(1) physical and chemical barriers,

such as epithelia and antimicrobialsubstances produced at epithelialsurfaces;

(2) phagocytic cells (neutrophils,macrophages) and NK(naturalkiller) cells;(3) blood proteins, includingmembers of the complementsystem and other mediators ofinflammation;

(4) proteins called cytokines thatregulate and coordinate many ofthe activities of the cells of innateimmunity.


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adaptive immunity

In contrast to innate immunity, there are other immuneresponses that are stimulated by exposure to infectiousagents and increase in magnitude and defensivecapabilities with each successive exposure to a particular

microbe. Because this form of immunity develops as a response toinfection and adapts to the infection, it is calledadaptive immunity.

The defining characteristics of adaptive immunity areexquisite specificity for distinct molecules and an abilityto "remember" and respond more vigorously to repeatedexposures to the same microbe. The adaptive immunesystem is able to recognize and react to a large numberof microbial and nonmicrobial substances


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Innate and adaptive immune responses are components of anintegrated system of host defense in which numerous cells and

molecules function cooperatively.The mechanisms of innate immunity provide effective defense

against infections.. . . against whatever doesnt belong

Cancer Damage/injuryChemicals

Other

pathogens

Innate andadaptiveimmuneresponses


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Innate and adaptive immuneInnate and adaptive immune

responsesresponses HoweverHowever,, manymany pathogenicpathogenic microbesmicrobes havehave evolvedevolved totoresistresist innateinnate immunityimmunity,, andand theirtheir eliminationelimination requiresrequires thethepowerfulpowerful mechanismsmechanisms ofof adaptiveadaptive immunityimmunity..


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ThereThere areare twotwo importantimportant linkslinks

betweenbetween innateinnate immunityimmunity andandadaptiveadaptive immunityimmunity..

FirstFirst,, thethe innateinnate immuneimmuneresponseresponse toto microbesmicrobes stimulatesstimulates

adaptiveadaptive immuneimmune responsesresponses andandinfluencesinfluences thethe naturenature ofof thetheadaptiveadaptive responsesresponses..

SecondSecond,, adaptiveadaptive immuneimmuneresponsesresponses useuse manymany ofof thetheeffectoreffector mechanismsmechanisms ofof innateinnateimmunityimmunity toto eliminateeliminate microbesmicrobes,,andand theythey oftenoften functionfunction bybyenhancingenhancing thethe antimicrobialantimicrobialactivitiesactivities ofof thethe defensedefense

mechanismsmechanisms ofof innateinnate immunityimmunity..


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Types of Adaptive ImmuneTypes of Adaptive Immune

ResponsesResponses ThereThere areare twotwo typestypes ofof adaptiveadaptive immuneimmuneresponsesresponses,, calledcalled humoralhumoral immunityimmunity andandcellcell--mediatedmediated immunityimmunity,, thatthat areare mediatedmediated bybydifferentdifferentcomponentscomponents ofofthethe immuneimmune systemsystem andandfunctionfunction toto eliminateeliminate differentdifferent typestypes ofofmicrobesmicrobes

HumoralHumoralimmunityimmunity isis mediatedmediated byby moleculesmolecules inin thethebloodblood andand mucosalmucosal secretionssecretions,, calledcalled antibodiesantibodies,, thatthatareare producedproduced byby cellscells calledcalled BB lymphocyteslymphocytes((alsoalso calledcalledBB cellscells).).

AntibodiesAntibodies themselvesthemselves areare specializedspecialized,, andand differentdifferenttypestypes ofof antibodiesantibodies maymay activateactivate differentdifferent effectoreffectormechanismsmechanisms.. ForFor exampleexample,, somesome typestypes ofof antibodiesantibodiespromotepromote phagocytosisphagocytosis,, andand othersothers triggertrigger thethe releaserelease ofofinflammatoryinflammatory mediatorsmediators fromfrom leukocytesleukocytes suchsuch asas mastmastcellscells..


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specific immunity

In addition, it has an extraordinary capacity todistinguish among different, even closely related,microbes and molecules, and for this reason it is alsocalled specific immunity.

The components of adaptive immunity arelymphocytes and their products.


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CytokinesCytokines

CytokinesCytokines areare ;;

aa uniqueunique familyfamily ofof growthgrowth factorsfactors..

SecretedSecreted primarilyprimarily fromfrom leukocytesleukocytes TheyThey stimulatestimulate bothboth thethe humoralhumoral andand

cellularcellular immuneimmune responsesresponses, as, as wellwell asas

activationactivation ofof phagocyticphagocytic cellscells


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LymphokinesLymphokines;; cytokinescytokines areare secretedsecreted fromfromlymphocyteslymphocytes

MonokinesMonokines;; TheyThey areare secretedsecreted bybymonocytesmonocytes oror macrophagesmacrophages..

InterleukinsInterleukins ((ILsILs):): TheyThey areare notnot onlyonly secretedsecreted byby leukocytesleukocytes butbut

alsoalso ableable toto affectaffect thethe cellularcellular responsesresponses ofofleukocytesleukocytes..

TheyThey areare growthgrowth factorsfactors targetedtargeted toto cellscells ofof

hematopoietichematopoietic originorigin..


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Foreign substances that induce specificimmune responses or are the targets ofsuch responses are called antigens.


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The principal cells ofthe immune systemareThe principal cells ofthe immune systemarelymphocytes, antigenlymphocytes, antigen--presenting cells, andeffectorpresenting cells, andeffector

cells.cells.

LymphocytesLymphocytes areare thethe cellscells thatthat specificallyspecificallyrecognizerecognize andand respondrespond toto foreignforeign antigensantigensandand areare thereforetherefore thethe mediatorsmediators ofofhumoralhumoral andand cellularcellular immunityimmunity.. ThereThere arearedistinctdistinct subpopulationssubpopulations ofof lymphocyteslymphocytes

thatthat differdiffer inin howhow theythey recognizerecognize antigensantigensandand inin theirtheir functionsfunctions


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BB lymphocyteslymphocytes areare thethe onlyonly cellscells capablecapable ofof producingproducing antibodiesantibodies..

TheyThey recognizerecognize extracellularextracellular ((includingincluding cellcell surfacesurface)) antigensantigens andanddifferentiatedifferentiate intointo antibodyantibody--secretingsecreting cellscells,, thusthus functioningfunctioning asas thethemediatorsmediators ofof humoralhumoral immunityimmunity..

TT lymphocyteslymphocytes,, thethe cellscells ofof cellcell--mediatedmediated immunityimmunity,, recognizerecognize thethe antigensantigens ofof intracellularintracellular

microbesmicrobes andand functionfunction toto destroydestroy thesethese microbesmicrobes oror thethe infectedinfected cellscells. T. Tcellscells do notdo not produceproduce antibodyantibody moleculesmolecules.. TheirTheir antigenantigen receptorsreceptors arearemembranemembrane moleculesmolecules distinctdistinct fromfrom butbut structurallystructurally relatedrelated toto antibodiesantibodies ..

TT lymphocyteslymphocytes havehave aarestrictedrestricted specificityspecificity forfor antigensantigens;; theytheyrecognizerecognize onlyonly peptidepeptide antigensantigens attachedattached toto hosthost proteinsproteins thatthatareare encodedencoded byby genesgenes inin thethe majormajorhistocompatibilityhistocompatibility complexcomplex(MHC)(MHC) andand thatthat areare expressedexpressed onon thethe surfacessurfaces ofof otherothercellscells. As. Asaaresultresult,, thesethese TT cellscells recognizerecognize andand respondrespond toto cellcell surfacesurface--associatedassociated but notbut not solublesoluble antigensantigens..


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TT lymphocyteslymphocytes consistconsist ofof functionallyfunctionally distinctdistinctpopulationspopulations,, thethe bestbest defineddefined ofof whichwhich areare helperhelper TTcellscells andand cytolyticcytolytic,, oror cytotoxiccytotoxic, T, T lymphocyteslymphocytes((CTLsCTLs).).

InIn responseresponse toto antigenicantigenic stimulationstimulation,, helperhelper TT cellscellssecretesecrete proteinsproteins calledcalled cytokinescytokines,, whosewhose functionfunction isis totostimulatestimulate thethe proliferationproliferation andand differentiationdifferentiation ofof thethe TTcellscells themselvesthemselves, as, as wellwell asas otherother cellscells,, includingincluding BB cellscells,,macrophagesmacrophages,, andand otherother leukocytesleukocytes..

CTLsCTLs killkill cellscells thatthat produceproduce foreignforeign antigensantigens,, suchsuch asas

cellscells infectedinfected byby virusesviruses andand otherother intracellularintracellular microbesmicrobes.. SomeSome TT lymphocyteslymphocytes,, whichwhich areare calledcalled regulatoryregulatory TT cellscells,,

functionfunction mainlymainly toto inhibitinhibit immuneimmune responsesresponses.. TheThegenerationgeneration andand physiologicphysiologic rolesroles ofof thesethese regulatoryregulatory TTcellscells areare incompletelyincompletely understoodunderstood


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AA thirdthird classclass ofof lymphocyteslymphocytes,, naturalnatural killerkiller(NK)(NK) cellscells, is, is involvedinvolved inin innateinnate immunityimmunityagainstagainst virusesviruses andand otherother intracellularintracellularmicrobesmicrobes..


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TheThe initiationinitiation andand developmentdevelopment ofof adaptiveadaptive immuneimmuneresponsesresponses requirerequire thatthat antigensantigens bebe capturedcaptured andanddisplayeddisplayed toto specificspecific lymphocyteslymphocytes.. TheThe cellscells thatthat serveservethisthis rolerole areare calledcalled antigenantigen--presentingpresenting cellscells ((APCsAPCs).).

TheThe mostmost highlyhighly specializedspecialized APCsAPCs areare dendriticdendritic cellscells,,whichwhich capturecapture microbialmicrobial antigensantigens thatthat enterenter fromfrom thetheexternalexternal environmentenvironment, transport, transport thesethese antigensantigens toto

lymphoidlymphoid organsorgans,, andand presentpresent thethe antigensantigens toto naivenaive TTlymphocyteslymphocytes toto initiateinitiate immuneimmune responsesresponses..


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MHC stands for major histocompatibilityMHC stands for major histocompatibilitycomplex (also called HLA in humanscomplex (also called HLA in humans --

human lymphocyte antigen), which is ahuman lymphocyte antigen), which is aset of genetic loci that code for the MHCset of genetic loci that code for the MHCmolecules that are an important set of cellmolecules that are an important set of cellsurface markers found on most cells.surface markers found on most cells.


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The activation oflymphocytes by antigen

leads to the generation ofnumerous mechanisms thatfunction to eliminate theantigen.

Antigen elimination oftenrequires the participation of

cells called effectorcells.Activated T lymphocytes,mononuclear phagocytes,and other leukocytesfunction as effector cells indifferent immune responses.


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AdaptiveAdaptive immuneimmune responsesresponses maymay bebe divideddivided intointo distinctdistinct phasesphases

TheThe recognitionrecognition ofof

antigenantigen thethe activationactivation ofof

lymphocyteslymphocytes,,

thethe effectoreffector phasephaseofof antigenantigeneliminationelimination--followedfollowed byby thethereturnreturn totohomeostasishomeostasis andand

thethe maintenancemaintenanceofof memorymemory


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Antigen presentationAntigen presentation

Antigen-presenting cells

(APCs) may be

macrophages or B cells

T cells only recognize an antigen if it is bound to theMHC molecules on the surface of an antigen-

presenting cell (APC).

An APC ingests antigens and partially digests them.

Peptide fragments are then displayed on the MHC

molecules on the surface of the APC.

T cells have special antigen-recognizingmolecules on theirsurfaces called T cell receptors

(TCR).

it is possible for several different T cells to become

activated in response to different fragments of the

same antigen.

An APC that has ingested antigen presentspieces of the Ag on MHC molecules to T cell by

docking with its TCR. This, and a 2nd signal,

activates the T cell.


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APCs may also include B cells. PeptideAPCs may also include B cells. Peptideantigen is presented by MHC but theantigen is presented by MHC but thewhole antigen may also be bound to thewhole antigen may also be bound to theB cells specific surface antibodyB cells specific surface antibodymolecules.molecules.

Antigen presentation alone is not enoughAntigen presentation alone is not enoughto effectively activate T cells. A secondto effectively activate T cells. A secondsignal or cosignal or co--stimulatory molecule isstimulatory molecule isreleased by the APC. This moleculereleased by the APC. This moleculeinteracts with another molecule on the Tinteracts with another molecule on the Tcell surface, reinforcing the first signalcell surface, reinforcing the first signal

and completing the activation of the Tand completing the activation of the T

cellcell..


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T cell activationT cell activation

Presentation of antigen to a

T cell triggers its activation

into a helper T (TH) cell.

Activated TH cells produce

a cytokine called

interleukin-2 (IL-2). IL-2

causes the T cells to divide.Some of the new T cells go

into battle (TH effector cells)

and some become memory

cells.

Activated T helper

cells induceeffectorand

memory TH cells


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B cell activation andB cell activation anddifferentiationdifferentiation

. When a T cell with a corresponding T cell receptor(TCR) interacts with the antigen fragment, the T cell

produces cytokines, thereby activating the B cell.

Activated T cells interact with B cells through the

action of cytokines. The B cells become activated

and differentiate into plasma cells. Plasma cellssecrete antibodies, which help to inactivate the

antigen.

An activated B cell may become either a memory B cell

or a plasma cell. A memory cell can produce antibody

(IgG) earlier than unactivated B cells and usually has

surface antibodies that interact strongly with antigen.

A plasma cell is characterized by an enormous amount

of endoplasmic reticulum, reflecting the fact that it

produces large amounts of a single specific protein

(antibody). Plasma cells have a lifespan of only a few

days.

Activated T

helpercell

Antibodies


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AtAt thethe endend of anof an immuneimmune responseresponse,, thethe immuneimmune systemsystemreturnsreturns toto itsits basalbasal restingresting statestate, in, in largelarge partpart becausebecause mostmostofof thethe progenyprogeny ofof antigenantigen--stimulatedstimulated lymphocyteslymphocytes diedie byby

apoptosisapoptosis..


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Cytokine is a general term for a large and diverseCytokine is a general term for a large and diverse

group of soluble messenger proteins.group of soluble messenger proteins.

These include theThese include the interferonsinterferons, interleukins, colony, interleukins, colony

stimulating factors and tumor necrosis factors. They arestimulating factors and tumor necrosis factors. They areproduced by a wide variety of activated immune cellsproduced by a wide variety of activated immune cells

(resting cells do not produce cytokines), as well as by(resting cells do not produce cytokines), as well as by

cells outside the immune system.cells outside the immune system.

Their effects vary widely. Some cytokines have similarTheir effects vary widely. Some cytokines have similar

effects and reinforce one another, while others haveeffects and reinforce one another, while others haveopposing effects and help to regulate responsesopposing effects and help to regulate responses


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EGF actsby binding with highEGF actsby binding with high affinityaffinitytoto epidermalepidermal growthgrowth factorfactor receptorreceptor(EGFR)on the(EGFR)on the cellcell surfacesurface andandstimulating the intrinsic proteinstimulating the intrinsic protein--tyrosinetyrosine kinasekinase activity of theactivity of thereceptorreceptor..

EEpidermalpidermal GGrowthrowth FFactoractor

id l h fid l h f


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TheThe epidermalepidermal growthgrowth factorfactorreceptorreceptor ((HERHER--1 or ERBB11 or ERBB1)) familyfamilyconsistsconsists of4of4 closelyclosely relatedrelatedtransmembranetransmembrane receptorsreceptors::

HERHER--1/EGFR,1/EGFR,

HERHER--2,2,

HERHER--3,3,

andand HERHER--4.4.

EachEach receptorreceptor has anhas an extracellularextracellular

ligandligand--bindingbinding domain,domain, aa transmembranetransmembrane regionregion thatthat

anchorsanchors thethe receptorreceptor toto thethe cellcell,,

andand anan intracellularintracellular cytoplasmiccytoplasmicdomaindomain thatthat containscontains aa tyrosinetyrosine

kinasekinase regionregion andand aa carboxycarboxyterminalterminal tailtail..

epidermal growth factorepidermal growth factorreceptorreceptor


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epidermal growth factorepidermal growth factor BindingBinding ofof ligandsligands toto thethe extracellularextracellular domaindomain

resultsresults inin receptorreceptor oligomerizationoligomerization,, activationactivationofof thethe receptor'sreceptor's tyrosinetyrosine kinasekinase activity,activity, andandreceptorreceptor autophosphorylationautophosphorylation inin severalseveral CCterminalterminal tyrosinetyrosine residuesresidues..

EGFsEGFs tyrosinetyrosine kinasekinase activityactivity initiatesinitiates aasignalsignal transductiontransduction cascadecascade thatthat resultsresults

inin aa varietyvariety ofof biochemicalbiochemical changeschangeswithinwithin thethe cellcell

aa riserise inin intracellularintracellular calciumcalcium levelslevels

increasedincreased gycolysisgycolysis andand proteinproteinsynthesissynthesis

increasesincreases inin thethe expressionexpression ofof certaincertaingenesgenes includingincluding thethe genegene forfor EGFREGFR

The activation of these pathwaysThe activation of these pathwaysdownstream of the EGFR leads todownstream of the EGFR leads tocell proliferation, differentiation, andcell proliferation, differentiation, andmigration or motility and adhesion,migration or motility and adhesion,protection from apoptosis, enhancedprotection from apoptosis, enhanced

survival, and gene transcription.survival, and gene transcription.


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AdvancedAdvanced understandingunderstanding of of intracellularintracellularsignalingsignaling processesprocesses responsibleresponsible forfortransformationtransformation andand tumortumor progressionprogression hashas

enabledenabled identificationidentification ofof potentialpotential therapeutictherapeutictargetstargets..


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The HER (The HER (erbBerbB) family of receptor tyrosine) family of receptor tyrosinekinaseskinases is one of theis one of the cytostaticcytostatic targets intargets intumor cell growth and survival.tumor cell growth and survival.

The HER (The HER (erbBerbB) family of) family of transmembranetransmembranereceptor tyrosinereceptor tyrosine kinaseskinases plays a pivotalplays a pivotalrole in normal cell growth, repair, androle in normal cell growth, repair, and

functional differentiation.functional differentiation.


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OverexpressionOverexpression of EGFR is recognized inof EGFR is recognized inmore than 80% ofmore than 80% of squamoussquamous cell cancers,cell cancers,and thisand this overexpressionoverexpression is associated withis associated witha poor prognosis.a poor prognosis.


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PlateletPlatelet DerivedDerived GrowthGrowth FactorFactor

(PDGF)(PDGF) --composedcomposed ofof twotwo distinctdistinct polypeptidepolypeptide chainschains (A,(A, B)B) FormForm homodimershomodimers (AA(AA oror BB)BB) oror heretodimersheretodimers (AB)(AB)..

OnlyOnly thethe dimericdimeric formform ofof PDGFPDGF interactinteract withwith PDGFPDGFreceptorreceptor..

LikeLike EGFREGFR ,, thethe PDGFRPDGFR havehave intrinsicintrinsic tyrosinetyrosine kinasekinaseactivityactivity.. FollowingFollowing autophosphorylationautophosphorylation ofof thethe PDGFPDGF

receptorreceptor,, numerousnumerous signalsignal--transducingtransducing proteinsproteinsassociateassociate withwith thethe receptorreceptor andand areare subsequentlysubsequentlytyrosinetyrosine phosphorylatedphosphorylated


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PlateletPlatelet DerivedDerived GrowthGrowth FactorFactor

(PDGF)(PDGF) ProliferativeProliferative responsesresponses toto PDGFPDGF actionaction areare exertedexerted ononmanymany mesenchymalmesenchymal cellcell typestypes..

OtherOther growthgrowth relatedrelated responsesresponses toto PDGFPDGF includeinclude

cytoskeletalcytoskeletal rearrangementrearrangement andand increasedincreasedpolyphosphoinositolpolyphosphoinositol turnoverturnover..

AgainAgain likelike EGF,EGF, PDGFPDGF inducesinduces thethe expressionexpression ofof aanumbernumber ofof nuclearnuclear localizedlocalized protooncogenesprotooncogenes,, suchsuch asasFos,Fos, mycmyc,, andand junjun..

TheThe primaryprimary effectseffects ofof TGFTGF--betabeta areare duedue toto thetheinductioninduction,, byby TGFTGF--beta,beta, ofof PDGFPDGF expressionexpression


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Fibroblast Growth Factors(FGFs)Fibroblast Growth Factors(FGFs)

There are 7 dstinct members of the FGF family of growth factors.There are 7 dstinct members of the FGF family of growth factors.

The predominant effect of FGF is to increase the growth ofThe predominant effect of FGF is to increase the growth ofendothelial cells; however, proliferative effects are observed on aendothelial cells; however, proliferative effects are observed on anumber of other cells of mesodermal and neuroectodermal origin.number of other cells of mesodermal and neuroectodermal origin.

FGFs also are neurotrophic for cells of both the peripheral andFGFs also are neurotrophic for cells of both the peripheral andcentral nervous system. Additionally, several members of the FGFcentral nervous system. Additionally, several members of the FGFfamily are potent inducers of mesodermal differentiation in earlyfamily are potent inducers of mesodermal differentiation in earlyembryos.embryos.

NonNon--proliferative effects include regulation of pituitary and ovarianproliferative effects include regulation of pituitary and ovarian

cell functioncell function..


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The FGF receptor has intrinsic tyrosine kinaseThe FGF receptor has intrinsic tyrosine kinaseactivity like both the EGF and PDGFactivity like both the EGF and PDGFreceptors. As with all transmembranereceptors. As with all transmembrane

receptors that have tyrosine kinase activity,receptors that have tyrosine kinase activity,autophosphorylation of the receptor is theautophosphorylation of the receptor is theimmediate response to FGF binding.immediate response to FGF binding.

Following activation of the FGF receptor,Following activation of the FGF receptor,

numerous signalnumerous signal--transducing proteinstransducing proteinsassociate with the receptor and becomeassociate with the receptor and becometyrosinetyrosine--phosphorylated.phosphorylated.


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Transforming Growth FactorsTransforming Growth Factors--FF (TGFs(TGFs--FF))

TGFTGF--FF waswas originallyoriginally charecterizedcharecterized as a protein (as a protein (secretedsecreted fromfrom aatumortumor cellcell lineline)) thatthat waswas capablecapable ofof inducinginducing aa transformedtransformedphenotypephenotype inin nonnon--neoplasticneoplastic cellscells inin cultureculture.. ThisThis effecteffect waswasreversiblereversible, as, as demonstrateddemonstrated byby thethe reversionreversion ofof thethe cellscells toto a normala normalphenotypephenotype followingfollowing removalremoval ofof thethe TGFTGF--FF..

SubsequentlySubsequently,, manymany proteinsproteins homologoushomologous toto TGFTGF--FF havehave beenbeenidentifiedidentified.. TheThe fourfour closestclosest relativesrelatives areare TGFTGF--FF1(1(thethe originaloriginal TGFTGF--FF))throughthrough TGFTGF--FF5(TGF5(TGF--FF1=TGF1=TGF--FF4).4). AllAll fourfour thesethese proteinsproteins shareshareextensiveextensive regionsregions ofof similaritysimilarity inin theirtheir aminoamino acidsacids..

ManyMany otherother proteinsproteins,, possesingpossesing distinctdistinct biologicalbiological functionsfunctions,, havehavestrechesstreches of aminoof amino acidacid homologyhomology toto thethe TGFTGF--FF familyfamily ofof proteinsproteins,,particularlyparticularly thethe CC--terminalterminal regionregion ofof thesethese proteinsproteins..

TheThe TGFTGF--FF relatedrelated familyfamily ofof proteinsproteins includesincludes thethe activinactivin andand inhibininhibinproteinsproteins.. IndeedIndeed,, thethe TGFTGF--FF familyfamily maymay comprisecomprise asas manymany as 60as 60 distinctdistinct

proteinsproteins,, allall withwith atat leastleast oneone regionregion of aminoof amino--acidacid sequencesequencehomologyhomology..


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There are several classes of cellThere are several classes of cell--surfacesurfacereceptors that bind different TGFsreceptors that bind different TGFs--FF withwithdiffering affinities. There also are celldiffering affinities. There also are cell--typetypespecific differences in receptor subtypes.specific differences in receptor subtypes.Unlike the EGF, PDGF and FGF receptors,Unlike the EGF, PDGF and FGF receptors,the TGFthe TGF--FF family of receptors all havefamily of receptors all have

intrinsic serine/threonine kinase activityintrinsic serine/threonine kinase activityand induce distinct cascades of signaland induce distinct cascades of signaltransduction.transduction.


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TGFs have proliferative effects on many mesenchymalTGFs have proliferative effects on many mesenchymaland epithelial cell types.and epithelial cell types.

Under certain conditions TGFUnder certain conditions TGF--FF will demonstrate antiwill demonstrate anti--

proliferative effects on endothelial cells, macrophagesproliferative effects on endothelial cells, macrophagesand Tand T-- and B lymphocytes.and B lymphocytes.

Such effects include decreasing the secretion ofSuch effects include decreasing the secretion ofimmunoglobulin and supressing hematopoiesis,immunoglobulin and supressing hematopoiesis,myogenesis, adipogenesis and adrenal steroidogenesis.myogenesis, adipogenesis and adrenal steroidogenesis.

Several members of the TGFSeveral members of the TGF--FF family are potentfamily are potentinducers of mesodermal differentiation in early embryos,inducers of mesodermal differentiation in early embryos,in particular TGFin particular TGF--FF2 and activin A.2 and activin A.


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Transforming Growth FactorTransforming Growth Factor--EE (TGF(TGF--EE))

TGFTGF--EE, like the, like the FF form, was first identified as a substance seceretedform, was first identified as a substance seceretedfrom certain tumor cells that, in conjunction with TGFfrom certain tumor cells that, in conjunction with TGF-- FF1, could1, couldreversibly transform certain types of normal cells in culture. TGFreversibly transform certain types of normal cells in culture. TGF--EEbinds to the EGF receptor, as well as its own distinct receptor, and itbinds to the EGF receptor, as well as its own distinct receptor, and itis this interaction that is thought to be responsible for the growthis this interaction that is thought to be responsible for the growthfactors effect. The predominant sources of TGFfactors effect. The predominant sources of TGF-- EE are carcinomasare carcinomasbur activated macrophages and keratinocytes ( and possibly otherbur activated macrophages and keratinocytes ( and possibly otherepithelial cells ) also secrete TGFepithelial cells ) also secrete TGF--EE. In normal cell populations, TGF. In normal cell populations, TGF--EE is a potent keratinocyte growth factor; forming an autocrineis a potent keratinocyte growth factor; forming an autocrinegrowth loop by virtue of the protein activating the very cells tahtgrowth loop by virtue of the protein activating the very cells taht

produce it.produce it.


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Erythropoietin (EPO)Erythropoietin (EPO) EPO is synthesized by the kidney and is the primaryEPO is synthesized by the kidney and is the primary

regulator of erythropoiesis. EPO stimulates the proliferationregulator of erythropoiesis. EPO stimulates the proliferationand differentiation of immature erythrocytes; it alsoand differentiation of immature erythrocytes; it alsostimulates the growth of erythroid progenitor cells (e.g.stimulates the growth of erythroid progenitor cells (e.g.Erythrocyte burst forming and colony forming units) andErythrocyte burst forming and colony forming units) and

induces the differentiation of erythrocytes colonyinduces the differentiation of erythrocytes colony--formingformingunits into proerythroblasts. When patients suffering fromunits into proerythroblasts. When patients suffering fromanemia due to kidney failure are given EPO, the result is aanemia due to kidney failure are given EPO, the result is arapid and significant increase in red blood cell count.rapid and significant increase in red blood cell count.


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InsulinInsulin--Like Growth FactorLike Growth Factor--II(IGF(IGF--I)I) IGFIGF--I (originally called somatomedin C) is a growth factorI (originally called somatomedin C) is a growth factor

structurally related to insulin. IGFstructurally related to insulin. IGF--I is the primary protein involvedI is the primary protein involvedin responses of cells to growth hormone (GH); that is , IGFin responses of cells to growth hormone (GH); that is , IGF--I isI isproduced in response to GH and then induces subsequent cellularproduced in response to GH and then induces subsequent cellularactivities, particulary on bone growth. It is the activity of IGFactivities, particulary on bone growth. It is the activity of IGF--I inI inresponse to GH that gave rise to the term somatomedin.response to GH that gave rise to the term somatomedin.Subsequent studies ghave demonstrated, however, That IGFSubsequent studies ghave demonstrated, however, That IGF--I hasI hasautocrine and paracrine activities in addition to the initially observedautocrine and paracrine activities in addition to the initially observedendocirne activities on bone.endocirne activities on bone.

The IGFThe IGF--I receptor, like the insulin receptor, has intrinsic tyrosineI receptor, like the insulin receptor, has intrinsic tyrosine

activity. Owing to their structural similarities IGFactivity. Owing to their structural similarities IGF--I can bind to theI can bind to theinsulin receptor but does so at a much lower affinity than doesinsulin receptor but does so at a much lower affinity than doesinsulin itself.insulin itself.


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InsulinInsulin--Like Growth FactorLike Growth Factor--IIII(IGF(IGF--II)II)

IGFIGF--II is almost exclusively expressed inII is almost exclusively expressed inembriyonic and neonatal tissues. Followingembriyonic and neonatal tissues. Followingbirth,the level of detectable IGFbirth,the level of detectable IGF--IIIIproteinfalls significantly.For this reasonproteinfalls significantly.For this reasonIGFIGF--II is thought to be a fetal growthII is thought to be a fetal growthfactor. The IGFfactor. The IGF--II receptor is identical toII receptor is identical to

the mannosethe mannose--6 phosphate receptor that is6 phosphate receptor that isresponsible for integration of lysosomalresponsible for integration of lysosomalenzymes (which contain mannoseenzymes (which contain mannose--66--phosphate residues) to the lysosomes.phosphate residues) to the lysosomes.


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CYTOKINESCYTOKINESILIL--II

ILIL--1 is1 is oneone themostthemost importantimportant immuneimmune responseresponse--modifyingmodifying

interleukinsinterleukins.. TheThe predominantpredominant functionfunction of ILof IL--1 is1 is toto enhanceenhance thetheactivationofactivationof TT--cellscells inin responseresponse toto antigenantigen..TheThe activationactivation of Tof T--cellscells,, byby ILIL--1,1,leadsleads toto incerasedincerased TT--cellcell productionproduction of ILof IL--22 andand ofofthethe ILIL--22 receptorreceptor,, whichwhich inin turnturn augmentsaugments thethe activationactivation ofof thethe TT--cellscells in anin an autocrineautocrine looploop,IL,IL--11 alsoalso inducesinduces expressionexpression ofofinterferoninterferon--gamma (IFNgamma (IFN--KK)) byby TT--cellscells..

ThisThis effecteffect of Tof T--cellcell activationactivation byby ILIL--11

ismimickedismimicked byby TNFTNF--EE whichwhichisis anotheranother cytokinecytokine secretedsecreted byby activatedactivated macrophagesmacrophages..ThereThere areare22 distinctdistinct ILIL--1proteins,1proteins,termedtermed ILIL--11EE andand 11--,,thatthat areare 26%26%homologoushomologous atat thethe aminoamino acidacid levellevel.. TheThe ILIL--1s1s areare secretedsecretedprimarilyprimarily byby macrophagesmacrophages butbut alsoalso fromfrom neutrophilsneutrophils,,endothelialendothelialcellscells,, smoothsmooth musclemuscle,,glialglial cellscells,,astrocytesastrocytes,B,B-- andand TT--cellscells,,fibroblastsfibroblastsandand keretinocyteskeretinocytes..ProductionProduction of ILof IL--11 byby thesethese differentdifferent cellcell typestypes

occursoccurs onlyonly inin responseresponse toto cellularcellular stimulationstimulation..InIn additionaddition toto itsitseffectseffects on Ton T cellscells,IL,IL--1 can1 can induceinduce proliferationproliferation inin nonnon--lymphoidlymphoidcellscells..


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ILIL--22

ILIL--2,2,producedproduced andand secretedsecreted byby activatedTactivatedT--cellscells,is,is thethe majormajorinterleukininterleukin responsibleresponsible forclonalforclonal TT--cellproliferationcellproliferation ILIL--22 alsoalso exertsexertseffectseffects on Bon B--cellscells,, macrophagesmacrophages,, andand naturalnatural killer (NK)killer (NK)cellscells..TheTheproductionproduction of ILof IL--22 occursoccurs primarilyprimarily byby CD4+ TCD4+ T--helperhelper cellscells.. TheTheexpressionexpression ofof bothboth ILIL--22 andand ILIL--22 receptorreceptor byby TT--cellscells isinducedisinduced byby ILIL--1.1. IndeedIndeed,,thethe ILIL--22 receptorisnotreceptorisnot expressedexpressed onon thethe surfacesurface ofofrestingTrestingT--cellscells andand isis presentpresent onlyonly transientlytransiently onon thethe surfacesurface of Tof T--cellscells,, disappearingdisappearing withinwithin 66--1010 daysdays ofof antigenantigen presentationpresentation..InIncontrastcontrast toto TT--helperhelper cellscells,,NkcellsNkcells constituvelyconstituvely expressexpress ILIL--22 receptorsreceptorsandand willwill secretesecrete TNFTNF--EE, IFN, IFN--KK andand GMGM--CSF inCSF in responseresponse toto ILIL--22

,,whichwhich inin turnactivateturnactivate macrophagesmacrophages..


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ILIL--66

ILIL--6 is6 is producedproduced byby macrophagesmacrophages,, fibroblastsfibroblasts,, endothelialendothelial cellscells andandactivatedactivated TT--helperhelper cellscells. IL. IL--66 actsacts inin synergysynergy withwith ILIL--II andand TNFTNF--EE ininmanymany immuneimmune responsesresponses,,includingincluding TT--cellcell activationactivation.. InIn particularparticular,,ILIL--6 is6 is thethe primaryprimary inducerinducer ofof thethe acuteacute--phasephase responseresponse inin liverliver. IL. IL--66alsoalso enhancesenhances thethe differentiationdifferentiation of Bof B--cellscells andand theirtheir consequentconsequentproductionproduction ofof immunoglobulinimmunoglobulin..GlucocorticoidGlucocorticoid synthesissynthesis isis alsoalsoenhancedenhanced byby ILIL--6.6.UnlikeUnlike, IL, IL--I, ILI, IL--22 andand TNFTNF-- EE,IL,IL--66 doesdoes notnotinduceinduce cytokinecytokine expressionexpression;;itsits mainmain effectseffects,, thereforetherefore,, aretoareto

augmentaugment thethe responsesresponses ofof immuneimmune cellscells toto otherother cytokinescytokines..


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ILIL--88

ILIL--8 is an interleukin that belongs to an8 is an interleukin that belongs to aneverever--expanding family of proteins thatexpanding family of proteins thatexert chemoattactant activity toexert chemoattactant activity toleukocytes and fibroblasts. This family ofleukocytes and fibroblasts. This family ofproteins is termed the cytokines. ILproteins is termed the cytokines. IL--8 is8 isproduced by monocytes, neutrophils, andproduced by monocytes, neutrophils, and

NK cells and chemoattactant forNK cells and chemoattactant forneutrophils, basophils and Tneutrophils, basophils and T--cells.Incells.Inaddition,ILaddition,IL--8 activates neutrophils to8 activates neutrophils todegranulate.degranulate.


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Tumor Necrosis FactorTumor Necrosis Factor--EE (TNF(TNF--EE))

TNFTNF-- EE(cachectin) like IL(cachectin) like IL--I isamajor immune responseI isamajor immune response-- modifyingmodifyingcytokine produced primarily by activated macrophages. Like ILcytokine produced primarily by activated macrophages. Like IL--I,I,TNFTNF-- EE induces the expression of other autocrine growth factors,induces the expression of other autocrine growth factors,increases cellular responsiveness to growth factors and inducesincreases cellular responsiveness to growth factors and inducessignaling pathways that lead to proliferation.TNFsignaling pathways that lead to proliferation.TNF-- EE actsactssynergistically with EGF and PDGF on some celltypes.Like othersynergistically with EGF and PDGF on some celltypes.Like othergrowth factors, TNFgrowth factors, TNF-- EE induces expression of a number of nuclearinduces expression of a number of nuclear

protoproto--oncogenes as well as of several interleukinsoncogenes as well as of several interleukins..


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Tumor Necrosis FactorTumor Necrosis Factor-- (TNF(TNF--))

TNFTNF-- (lymphotoxin) is charecterized by its ability to kill a number(lymphotoxin) is charecterized by its ability to kill a numberof different cell types, as well as the ability to induce terminalof different cell types, as well as the ability to induce terminaldifferentiation in others. One significant nondifferentiation in others. One significant non--proiferative response toproiferative response toTNFTNF-- is an inhibition of lipoprotein lipase present on the surface ofis an inhibition of lipoprotein lipase present on the surface ofvascular endothelial cells. The predominant site of TNFvascular endothelial cells. The predominant site of TNF-- synthesissynthesisis Tis T--lymphocytes, in paticular the special class of Tlymphocytes, in paticular the special class of T--cells calledcells calledcytotoxic Tcytotoxic T--lymphocytes (CTL cells)lymphocytes (CTL cells) . The induction of. The induction of expressionexpressionresults from elevations in ILresults from elevations in IL--2 as well as the interaction of antigen2 as well as the interaction of antigenwith Twith T--cell receptors.cell receptors.


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InterferonInterferon--KK (IFN(IFN--KK))

IFNIFN--EE, IFN, IFN-- and IFNand IFN--[[ are known as type I interferons: they areare known as type I interferons: they arepredominantly responsible for antipredominantly responsible for anti--viral activities of theviral activities of theinterferons.In contrast, IFNinterferons.In contrast, IFN--KK is a type II or immune interferon.is a type II or immune interferon.

Although , IFNAlthough , IFN--KK has antiviral activity it is significantly less active athas antiviral activity it is significantly less active atthis function than the type I IFNs. Unlike the type I IFNs, IFNthis function than the type I IFNs. Unlike the type I IFNs, IFN-- KK isisnot induced by infection nor by doublenot induced by infection nor by double--stranded RNAs. IFNstranded RNAs. IFN-- KK isissecreted primarily by CD8+ T cells. Nearly all cells express receptorssecreted primarily by CD8+ T cells. Nearly all cells express receptorsfor IFNfor IFN-- KK and respond to IFNand respond to IFN-- KK binding by increasing the surfacebinding by increasing the surfaceexpression of class I MHC proteins,thereby promoting theexpression of class I MHC proteins,thereby promoting thepresentation of antigen to Tpresentation of antigen to T--helper (CD4+) cells. IFNhelper (CD4+) cells. IFN-- KK alsoalso

increases the presentation of class II MHC proteins on class II cellsincreases the presentation of class II MHC proteins on class II cellsfurther enhancing the ability of cells to present antigen to Tfurther enhancing the ability of cells to present antigen to T--cells.cells.


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Colony Stimulation FactorsColony Stimulation Factors(CSFs)(CSFs)

CSFs are cytokines that stimulate the proliferation of specificCSFs are cytokines that stimulate the proliferation of specificpluripotent stem cells of the bone marrow in adults. Granulocytepluripotent stem cells of the bone marrow in adults. Granulocyte--CSF (GCSF (G--CSF) is specific for proliferative effects on cells of theCSF) is specific for proliferative effects on cells of thegranulocyte lineage. Macrophagegranulocyte lineage. Macrophage--CSF (MCSF (M--CSF) is specific for cells ofCSF) is specific for cells ofthe macrophage lineage. Granulocytethe macrophage lineage. Granulocyte macrophagemacrophage--CSF (GMCSF (GM--CSF)CSF)has proliferative effects on both classes of lymphoid cells.EPO is alsohas proliferative effects on both classes of lymphoid cells.EPO is alsoconsidered aCSF aswell as a growth factor, since it stimulates theconsidered aCSF aswell as a growth factor, since it stimulates theproliferation of erythrocyte colonyproliferation of erythrocyte colony--forming units. ILforming units. IL--3(secreted p3(secreted pprimarily from Tprimarily from T--cells ) is alsoknown as multicells ) is alsoknown as multi--CSF, since it stimulatesCSF, since it stimulates

stem cells to produce all forms of hematopoietic cellsstem cells to produce all forms of hematopoietic cells..

cellular regulation son2.10.09

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