Cellsignalingnotes

Therearetwocomponentsofinductiveinteraction.Firstistheinducer,thetissuethatproduce
signalthatchangesthecellularbehaviouroftheothertissueandthesecondcomponentisthe
tissuebeinginducedthatistheresponder.Theabilitytorespondtothespecificsignalis
calledcompetence.Notalltissuescanrspondtothesignalbeinginduces.Forinstanceifoptic
vesicleofXenopusLaevisisplacedinanectopiclocation[indifferentplacefromwhereit
normallyis]underneaththeheadectoderm,itwillinducetheectrodermtoformthelens
tissue.Onlytheopticvesicleappearstodothis,thereforeitisaninducer.However,ifthe
opticalvesicleisplacesbeneathectodermintheflankorabdomenofthesameorganism,that
ectodermwillbeabletoformthelenstissue.Onlytheheadectodermincompetenttorespond
tothesignalsfromtheopticvesiclebyproducingalens. Competenceisactivelyacquired
condition.
Recombinationistheprocessusedtocheckwhetherparticulartypeofgeneishomozygous..
Whencellmembraneproteinsononecellinteractwithreceptorproteinsonadjacentcell
surfaces, these events are called juxtacrine interactions[since the cell membranes are
juxtaposed].Whenproteinssynthesizedbyonecellcandiffuseoversmalldistancetoinduce
changesinneighbouringcells,theeventiscalledparacrineinteraction.Thediffusibleproteins
are called paracrina factors or growth and differentiation factor [ GDFs]. Endocrine
factors[hormones]travelthroughthebloodtoexerttheireffects,paracrinefactorsaresecreted
intotheimmediatespacearoundthecellproducingthem.Theseproteinsaretheinducting
factos of the classical experimental embryologist. Many of the paracrine factors can be
groupedunder4familiesonthebasisoftheirstructures:
1.
2.
3.
4.

thefibroblastgrowthfactos[FGF]family
thehedgehogfamily
thewinglessorWntfamily
theTGFsuperfamily,encompassingtheTGFbfamily,theactivinfamily,BMPs,
Vg1familyandseveralotherproteins.

Thereisalsoautocrineregulationwhichoccursinthesamecellsthatsecretparacrinefactors
alsorespondtothem.Inotherwords,thecellsynthesizesthemoleculeforwhichithasits
ownreceptors.
Signaltransductioncascades:theresponsetoinducers
Paracrinefactorsbindstoreceptorinitiateacascadeoftenhavedifferentendpoints
like morphology change or different gene expression in cell called signal transduction
cascade.
Receptor tyrosine kinaseligand binds to receptor induce conformational change in
cytoplasmicdomainchangegiveittheenzymaticactivityusuallykinaseonethatcanuse
ATPtophosphorylatespecifictyrosineresiduesofparticularproteins. Theactivereceptor
cannowcatalysereactionsthatphosphorylateotherproteinsandthisphosphorylationin
turnactivateslatentactivitieseventuallyactivitatingthetranscriptionfactororcytoskeleton
protein[dormant]
RTKpathwayiscrucial,ligandthatbindtothistypeofreceptoraremostlythegrowthfactors
likeplateletsdrivefactors,growthfactors,stemcellsfactors.EachETKcanbindonlyoneor
a small set of these ligands. The RTK spans the cell membrane, binds to ligands,
conformationalchangealsotodimerizewithanotherRTKandactivatesthelatentkinase
activity of each RTK, these receptors phosphorylate each other on particular tyrosine

residues.Thusthebindingoftheligandcausestheautophosphorylationofthecytoplasmic
domainofthereceptor.
[RASpathwayexample]ThewidelyusedRTKtranductionpathway.Thereceptortyrosine
kinaseisdimerizedbytheligandwhichcausestheautophosphorylationofthereceptor.The
adaptor protein recognizes the phosphorylated tyrosines on the RTK and activates the
intermediateprotein,GNRPwhichactivatestheRasGproteinbyallowinthephosphorylation
of GDP bound ras. At the same time, the GAP protein stimulates the hydrolysis of this
phosphatebond,returningRastoitsinactiveform.TheactiveRasactivatedtheRafprotein
kinaseC[PKC],whichisturnsphosphorylatesseriesofkinases.FirstactivatesMEKthen
Eventually the activates kinase ERK alters the gene expression in the nucleus of the
responding cell by the phosphorylating certain transcription factors[ which can enter the
nucleustochangethegenestranscribes]andcertaintranslationfactors[whichalterthelevel
ofproteinsynthesis].Inmanycasesthispathwayisreinforcedbythereleaseofcalciumions.
GNRP=guaninenucleotidereleasingfactor.GAP=GTPaseactivatedprotein.
Thehedgehogfamilypathway
Functionsbythebindingtoareceptorcalledpatched.Thepatchedproteinisnotasignal
transducer butitis actuallyboundtothe signaltransducer i.e. Smoothened[S] protein.It
preventsSfromfunctioning.Intheabsenceofhedgehogbindingtopatched,Sisinactiveand
theCubitusinteruptus[Ci]proteinistetheredtothemicrotubules,itiscleavedinsuchaway
thattheportionofitentersthenucleusandactsasatranscriptionalrepressor.WhenHbinds
toP,thePproteinshapeisalteredsuchthatitnolongerinhibitsSprotein.Sacts[probablyby
phosphorylation]toreleasetheCiproteinfromthemicrotubulesandtoprecventitbeing
cleaves.TheintactCiproteincannowenterthenucelueswhereItactasatranscriptional
activatorofthesamegenesasitusedtorepress.Hpathwayisimportantinvertebratelimb
and neural differentiation. While mutation that inactivate the H pathway can cause the
malformation,theonethatactivatethispathwaycanectopicallycausecancer.IfPproteinis
mutatedinsomatictissuessuchthatitcannolongerinhibittheSprotein,itcancausetumors
ofthebasalcelllayerofepidermis.[3difftypesofhedgehoggene:sonic,greatestno.plus
biggestfunctionaswell,desertproteinexpressedinsertolicellsoftestis,andIndianHprotein
expressedinthegutandcartilageandisimpinpostnatalbonegrowth.
[FIGUREdescription]TheHsignaltransductionpathway.Pproteininthecellmembraneis
theinhibitoroftheSprotein.IntheabsenceofHbindingtotheP,theCiproteinistetheredto
themicrotubulesbytheCos2andfusedproteins.ThisbindingallowsthePKAandSlimb
proteinstocleaveCiintoatranscriptionalrepressorthatblockthetranscriptionofparticular
gene. When H binds to P, its conformational change release the inhibition of S, S then
releasesCifrommicrotubules[byaddingmorephosphatetotheCos2andfusedproteins]
andinactivatesthecleavageproteinsPKAandSlimb.TheCiproteinentersthenucleus,binds
aCBPproteinandactsasatranscriptionalactivatorofparticulargenes.
TheWntFamily[familyofcysteinerichglycoproteins]whilesonicheadgehogplaycrucial
roleinpatterningtheventralsideofsomites,thisfamilyplayimportantroleininducingthe
dorsalcellsofthesomitestobecomemusclesandbecomeinvolvedinthespecificationofthe
midbrain.Criticalinestablishingthepolarity,promotingtheproliferationofthestemcells,
several steps of urogenital development. The cononical Wnt pathway: members of this
paracrinefactorsinteractwithtransmembranereceptorsofthefrizzledfamilyofproteins.
BindingofWntcausesFrizzled[F]toactivatetheDisheveled[D]protein.OnceDproteinis
activated,itinhibitstheactivityoftheglycogensynthasekinase3[GSK3]enzyme.GSK3,if
weactivewouldpreventthedisassociationofthecatenin[C]proteinfromtheAPCprotein,
which targets [C] protein for degradation. However, when the Wnt signal is present and

GSK3isinhibited,[C}proteincandisassociatefromtheAPCproteinandenterthenucleus.
Onceinsidethenucleus,itcanformtheheterodimerwithanLEFandTCFDNAbinding
protein, becoming a transcription factor. This complex binds to and activates the Wnt
responsorgenes.[itscomponentshavemorethanonefunctionIthecell]GSK3:enzymethat
regulatesglycogenmetabolism,[C]proteinrecognizedaspartofcelladhesioncomplexon
surfacebeforebeingfoundasthetranscriptionalfactor.APCproteinplaysroleasatumor
suprressorprotein[coloncancerthoughttobecausedbyinabilityofthisproteintokeep[C]
out of the nucleus. OVERRIDING PRINCIPLE OF WNT AND H PATHWAY;
ACTIVATIONISOFTENACCOMPLISHEDBYINHIBITINGTHEINHIBITORS[figure
explanation:TheWntsignaltransductionpathway,thecanonicalWntpathwayinwhichWnt
proteinbindstoitsreceptor,amemberofFfamilyofproteins,whichactivatesDprotein
allowingIttobecomeaninhibitorofGSK3.GSK3ifactivewouldpreventdiassociation
of[C]proteinfromAPCprotein.SobyinhibitingGSK3,allows[C]toenternucleusassociate
withLEFotTCFproteintobecomeactivetranscriptionfactor.
TheTGFsuperfamily[transformationalgrowthfactors]MembersoftheTGFbfamily[T]
orparacrinefactorsactivatemembersoftheSmadfamilyoftranscriptionfactors.theTGFb
ligandbindstoatypeIITGFbreceptor,whichallowsthatreceptortobindtothetypeITGF
Breceptor.Oncethetworeceptorareinclosecontact,thetypeIIreceptorphosphorylatea
serineorthreonineonthetype1receptor,therebyactivatingit.TheactivatedtypeIreceptor
cannowphosphorylatetheSmadproteinsi.e.Smad1and5thatareactivatedbytheBMP
family of TGFB factors,while the receptor binding activin, Nodal and TGFB family
phosphorylateSmad2and3.ThesephosphorylatedSmadsbindstoSmad4andformthe
transcription factor complex that will enter the nucleus. FIGURE Explanation: the Smad
pathway,in[A]ansactivationcomplexisformedbythebindingoftheligandbythetype1
ans 2 receptors. This allows the type 2 recptor to phosphorylate the type 1 receptor on
particularserineandthreonineresidues[GSBOX]thephosphorylatedtype1receptorprotein
cannowphosphorylatetheSmadproteins.[B]thosereceptorsthatbindtheTGFBfamily
proteinsormembraneofactivinfamilyphosphorylateSmads2and3.Thosereceptorsthat
bindtoBMOfamilyproteinsphosphorylatesSmads1and5.TheseSmadscancomplexwith
Smad4toformactivetranscriptionfactors.
Deltanotchpathway:juxtaposedligandsandreceptors.[boundtoinducingcellsurface.in
onesuchpathwaycellexpressingthDelta,jaggedorSerrateProteinsIntheircellmembranes
activatetheirneighboringcellsthatcontainsthenotchproteinintheircellmembrane.Notch
extendsthroughthecellmembraneanditsexternalsurgacecontainsDelta,JaggedorSerrate
proteinsextendingoutfromanadjacentcell.Whencomplexedtooneoftheseligands,Notch
undergoesconformationalchangethatenablespartofitcytoplasmicdomaintobecutoffby
thepresenilin1protease. Thecleaved portionenters the nucleus and binds to a dormant
transcriptionfactoroftheCSIfamily.WhenbondtothenotchproteintheCSLtranscriptional
factorsactivatetheirtargetgenes.Activationisthoughttoinvolvetherecruitmentofhistone
acetyletransferase, thus notch is considered as transcriptional factor tethered to the cell
membrane.Whentheattachmentisbroken,Notch[orapieceofit]candetachfromthecell
membrane and enter the nucleus. [ extremely important in nervous system] [DIAGRAM
description[priortonotchsignaling,ACSLtranscriptionfactorisontheenhancerofNotch
regulatedgene.TheCSLbindsrepressorsoftranscription.[B]modelofactivationofnotch,
totheextracellulardomainofthenotchproteinonanadjacentcell.Thisbindingcausesa
shapechangeintheintracellulardomainofNotch,whichactivatetheprotease.TheProtease
cleavesNotchandallowstheintercellularregionoftheNotchproteintoenterthenucleusand
binftheSCLtranscriptionfactor.ThisintercellularregionofNotchdisplacestherepressor
proteinsandbindsactivatorsoftranscription,includinghistoneacetyltransferasep300.The
activatedCSLcanthentranscribeitstargetgene.

Integrin [ channels] Extracellular matrices are made up of collage, proteoglycan and

specializedglycoproteinmoleculessuchasFibronectinandlaminin[allowextraceullarand
intercellularscaffoldtoworktogether.
fibronectin:serveasgeneraladhesivemoleculelinkingcellstooneanotherandtoother
substratesuchasproteoglycansandcollagen.Havedistinctbindingsites,andtheirinteraction
withappropriatemoleculesresultintheproperalignmentofcellswiththeirextracellular
matrix.Alsohelpsincellmigration.Fibronectinpathleadgermcellstothegonadsandlead
heartcellstothemidlineoftheembryo.
Laminin: plays important role in assembling the extracellular matrix, promoting cell
adhesionandgrowth,changingcellshapeandpermittingcellmigration.
Gapjunctions:serveascommunicationchannelsbetweenadjacentcells.Cellsaidtocoupled
andsmallmoleculescanfreelypassfromonetoanother.