Growth factors

Growth Factors and their mechanism

1. GROWTH FACTORS
Dr. M. Sonia Angeline
Assistant Professor
KristuJayanti College

2. INTRODUCTIION
•GrowthFactorisaproteinmoleculemadebythebody;itfunctionstoregulatecelldivision&
cellsurvival.
•Growthfactorsbindtoreceptorsonthecellsurface,withtheresultofactivatingcellular
proliferationand/ordifferentiation,promotecellgrowth.
•Growthfactorsareproteinsthatfunctionasgrowthstimulators(mitogens)and/orgrowth
inhibitors,stimulatecellmigration,actaschemotacticagents,inhibitcellmigration,inhibit
invasionoftumorcells,modulatedifferentiatedfunctionsofcells,involvedinapoptosis,
involvedinangiogenesisandpromotesurvivalofcellswithoutinfluencinggrowthand
differentiation.
•ExamplesforGrowthFactorsareEGF,FGF,NGF,PDGF,VEGF,IGF,GMCSF,GCSF,TGF,
Erythropieitn.

3. GROWTH FACTORS
•GrowthFactorsarebiologicallyactivepoly-peptideswhichfunctionashormonelike
regulatorysignals,controllingthegrowthanddifferentiationofresponsivecells.The
distinctionbetweengrowthfactorsandhormonesisfrequentlyarbitrary.
•GrowthFactorsareinvolvedincelldifferentiationandareessentialtonormalcellcycle,
andarethusvitalelementsinthelifeofanimalsfromconceptiontodeath.
•GrowthFactorsmediatefetaldevelopment,playaroleinmaintenanceandrepairof
tissues,stimulateproductionofbloodcells&participateincancerousprocesses.
•Growthfactors,whichgenerallyconsideredasasubsetofcytokines,refertothediffusible
signalingproteinsthatstimulatecellgrowth,differentiation,survival,inflammation,and
tissuerepair.

5. •EGFstandsforEpidermalGrowthFactorwhichisaproteinfoundinbothhumansandother
animalssuchasmice.
•Whenpresentinhumans,it’softenlocatedinvarioustissuesofthebody.
•Twoofthemostcommonareasaretheparotidglandandsubmandibulargland.
•UpondiscoveringhumanEGFforthefirsttime,itwascalledurogastrone.
•Epidermalgrowthfactorisoftenfoundinvariousliquidsthroughoutthebody,particularly;urine,
milk,bloodplasma,andsaliva.
•Itisthoughtthatepidermalgrowthfactorisproducedlargelythankstotestosteronestimulation.
Assuch,it’softenmorecommonlypresentinmalebodiesthanfemale.
•Epidermalgrowthfactor(EGF)andEGFreceptor(EGFR)playanessentialroleinwoundhealing
throughstimulatingepidermalanddermalregeneration.
•Inaddition,EGFRinhibitors(EGFRis)havebecomeatherapeuticoptionforthetreatmentof
cancer.
EPIDERMAL GROWTH FACTOR (EGF)

6. FUNCTION & INTERACTIONS
•ThemainfunctionofEGFistohelpencouragecellgrowth.Itdoesthisbybindingwitha
receptorknownasEGFR.
•Whenthisbindingoccurs,itleadstoarapidincreaseinthecellcount,differentiationwithin
cells,andcellsurvival.
•ThisisparticularlyprevalentinsalivaryEGFproteins.
•WhenEGFisproducedinthesalivaryglands,itislinkedtomaintainingandrepairing
gastrictissue,alongwithoro-oesophagalmaintenance.Asaconsequence,manyproblems
withinthispartofthebodycanbehealedthankstoEGF.
•Thebestexampleofthisisulcersinthemouthandthroat,whichcanbehealedwhenthis
proteinissecreted

7. MECHANISM
•EGFactswhenitbindstoitsreceptor;EGFR.
•Thisbindingoccursonthesurfaceofthecell,andhelpsstimulateaprocesscalledligand-
induceddimerization.
•Whenthishappens,thereisareactionintheproteinthathelpsactivateit'sintrinsicprotein-
tyrosinekinaseproperties.
•Asaresult,thiswillthenturnonaprocessthattransmitsasignalthroughthecell,whichwill
endinvariouschangesinthecellonabiologicallevel.
•Themainthingsthathappenduringthistimeareanincreaseincalciumlevelswithinthe
cell,alongwithheightenedproteinsynthesisandglycolysis.
•Tocoincidewiththis,therearealsoincreasesincertaingeneexpressionsaswell

8. STRUCTURE
•The structure of EGF is somewhat similar to many other proteins as they’re all part of the
same family.
•In this sequence, there are a total of six cysteine residues that merge together to create
three intramolecular disulfidebonds.
•Consequently, the formation of these bonds leads to the creation of three structural loops.
•These structural loops have a high significance as they’re responsible for inducing high-
affinity binding that connects all EGF-family proteins to their cell-surface receptors.
•Epidermal growth factor is often referred to as a 6-kDa protein due to its structural makeup.
•As well as the six cysteine residues and three intramolecular disulfidebonds, there are also
53 amino acid residues present.

10. FIBROBLAST GROWTH FACTOR (FGF)
•Thefibroblastgrowthfactor(FGF)familyconsistsofstructurallyrelatedpolypeptidesinvolvedinseveral
physiologicprocesses.
•Highlyconserved,thesegrowthfactorsarefoundinthousandsofanimalspecies,ranging
fromnematodeandzebrafishtomouseandhuman.
•FGFsplayaroleincellularproliferation,migration,anddifferentiation,mitogenesis,angiogenesis,
embryogenesis,andwoundhealing.
•ItisbytheactivationofvarioussignaltransductionpathwaysthatFGFsmediatemultipledevelopmental
processes.
•Fibroblastgrowthfactors(FGF)andtheirreceptorsservemanyfunctionsinboththedevelopingand
adultorganism.Humanscontain18FGFligandsandfourFGFreceptors(FGFR).

11. MECHANISM
•Intheadult,FGFsandFGFRsarecrucialfortissuerepair.
•FGFsignalinggenerallyfollowsoneofthreetransductionpathways:RAS/MAPkinase,PI3/AKT,orPLCγ.
•Eachpathwaylikelyregulatesspecificcellularbehaviors.
•InappropriateexpressionofFGFandimproperactivationofFGFRsareassociatedwithvariouspathologic
conditions,unregulatedcellgrowth,andtumorigenesis.
•Additionally,aberrantsignalinghasbeenimplicatedinmanyskeletalabnormalitiesincludingachondroplasia
andcraniosynostosis.
•ThemajorityofFGF-relatedtherapyisaimedatage-relateddisorders.
•IncreasedunderstandingofFGFsignalingandbiologymayrevealadditionaltherapeuticroles,bothinutero
andpostnatally.

12. •FGFs mediate their cellular function through binding to and activating a family of Receptor Tyrosine Kinases
(RTKs), which are designated the high-affinity FGF receptors FGFR1 to FGFR5.
•FGFs also bind to heparin or Heparin Sulfate Proteoglycans (HSPG), low-affinity receptors that do not transmit a
biological signal; rather they function as accessory molecules that regulate FGF-binding and activation of the
FGFRs.
•Like all RTKs, functional FGFRs are transmembrane proteins composed of an extracellular ligand-binding
domain and a cytoplasmic domain containing the catalytic protein tyrosine kinase core.
•The extracellular ligand-binding domains of FGFRs are prototypically composed of three Ig-like domains.
•Alternative mRNA splicing of the Ig domains in FGFR1 through FGFR3 leads to distinct functional variants of
these receptors.
MECHANISM

13. FUNCTIONS
•FGF ligands are polypeptide growth factors that regulate several developmental processes includingcellular
proliferation, differentiation, and migration,morphogenesis, and patterning.
•FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton. In particular, the signaling
cascade has been implicated in intramembranous ossification of cranial bones as well as cranial
suturehomeostasis.
•Angiogenesis, the growth of new blood vessels, plays a key role in many physiological and pathological
processes, such as ovulation, embryogenesis, wound repair, inflammation, malignant tumor growth,
retinopathies, rheumatoid arthritis, and angiogenesis-dependent diseases.
•One of the best-characterized modulators of angiogenesis is the heparin-binding FGF (Fibroblast Growth
Factor).

14. FUNCTIONS
•FGFs are a large family of multifunctional peptide growth factors of which there are at least 28 distinct
members.
•The members of this peptide growth factor family have been identified in a variety of organisms and play
pivotal roles in many cellular processes including mitogenesis, differentiation, migration, and cell survival.
•During embryonic development, FGFs play a critical role in morphogenesis by regulating cellular
proliferation, differentiation, and migration.
•In the adult, FGFs are homeostatic factors functioning in tissue repair and wound healing, in the control of
the nervous system, and in tumor angiogenesis. FGF acts on a variety of different cell types, functioning as
both a direct and an indirect stimulator of angiogenesis.

15. PLATELET-DERIVED GROWTH FACTOR (PDGF)
•Platelet-derived growth factor(PDGF) constitutes a family of dimeric isoforms, acting
onconnective tissuecells and certain other cell types.
•PDGFwas originally discovered as a constituent of platelets, which are released into serum in
conjunction withblood coagulation.
•Although the α-granules of platelets are a major storage site for PDGF, PDGF is also
produced by many other cell types.
•PDGF stimulates the growth of its target cells, but also affectschemotaxis, i.e., directed cell
movement, and cell shape through reorganization of theactin filamentsystem.

16. PDGF
•PDGFalsoaffectsthedifferentiationofspecificcelltypesandpromotescellsurvival.
•Throughtheseeffects,PDGFhasimportantfunctionsincertainorgansduringembryonic
development,aswellasintheadultinthestimulationofwoundhealingandinthemaintenance
ofconnectivetissuehomeostasis.
•OveractivityofPDGFhasbeenlinkedtocertaindiseases,suchasmalignanciesinwhichPDGF
productionmaypromotetumorgrowthviaautocrineorparacrinestimulation.
•PDGFisalsoimplicatedinotherdisordersthatinvolveanexcessofcellproliferation,
e.g.,atherosclerosisandfibroticconditions.

17. MECHANISM
•PDGFisastimulatorofcelldivision(mitogen)fordifferentcelltypes,suchascellsinconnective
tissueanddevelopingnervoussystem.
•Ithasfivedifferentpolypeptidechains(subunits).
•ThePDGFsplayavitalroleinwoundhealingandareincreasinglybeingimplicatedinfibrosis.Originally
isolatedfromplatelets,PDGFisoformsarealsosecretedbymonocytesandmacrophages,endothelialcells,
andfibroblasts.
•SincePDGFsplayimportantrolesinregulatingthedifferentiation,proliferation,andsurvivalofmesenchymal
progenitorcells,dysregulatedPDGFsignalingplaysaroleinfibrosis.

18. FUNCTION
•PDGFisamemberofthehumangrowthfactorfamilythatregulatescellgrowthand
division.Itwasoriginallydiscoveredasaconstituentofwholebloodserum,absentin
cell-freeplasma-derivedserum.
•Subsequently,thisfactorwasisolatedfromhumanplatelets.Theprimarysourceof
thisfactorareα-granulatesfromactivatedplatelets.
•Manyothercells,however,alsoexpressthisfactor,includingfibroblasts,vascular
smoothmuscleandendothelialcells,macrophages,neuronsandmanyother.
•TheprimaryfunctionofPDGFisthegrowthcontrolofmesenchymalcellssuchas
fibroblastsandsmoothmusclecells.

19. ERYTHROPOIETIN
•Erythropoietin (EPO) is ahormoneproduced primarily by the kidneys, with small amounts made by
the liver.
•EPO plays a key role in the production of red blood cells (RBCs), which carry oxygen from the
lungs to the rest of the body.
•Erythropoietin promotes the formation ofred blood cellsby the bone marrow.
•The erythropoietin hormone level can be detected and measured in the blood (the EPO test).
•Measurement of the blood erythropoietin level can be used to detect certain medical conditions.
•Erythropoietin can be synthesized and used as a treatment of some forms ofanemia.
•Erythropoietin has been misused as a performance-enhancing drug by some athletes.

20. ERYTHROPOIETIN
•The body uses a dynamicfeedback systemto help maintain sufficient oxygen levels and
a relatively stable number of RBCs in the blood.
•Erythropoietin is produced and released into the blood by the kidneys in response to
low blood oxygen levels (hypoxemia). The amount of erythropoietin released depends
on how low the oxygen level is and the ability of the kidneys to produce erythropoietin.
•EPO is carried to thebone marrow, where it stimulates production of red blood cells.
The hormone is active for a short period of time and then eliminated from the body in
the urine.
•As oxygen levels in the blood rise to normal or near normal levels, the kidneys slow
production of EPO.

21. WHAT DOES ERYTHROPOIETIN DO? WHY DO
WE NEED IT?
•Erythropoietin stimulates the bone marrow to produce more red blood cells. The
resulting rise inred cellsincreases the oxygen-carrying capacity of the blood.
•As the prime regulator of red cell production, erythropoietin's major functions are to:
•Promote the development of red blood cells.
•Initiate the synthesis of hemoglobin, the molecule within red blood cells that transports
oxygen.
•Chemically, erythropoietin a protein with an attachedsugar(a glycoprotein). It is one of
a number of similar glycoproteins that serve asstimulantsfor the growth of specific
types of blood cells in the bone marrow.

22. ERYTHROPOIETIN
•However, if your kidneys are damaged and do not produce enough erythropoietin, then too
few RBCs are produced and you can becomes anemic.
•Similarly, if your bone marrow is unable to respond to the stimulation from EPO, then you
may become anemic.
•This can occur with somebone marrow disordersor withchronicdiseases, such
asrheumatoid arthritis.
•If you have a condition that affects the amount of oxygen you breathe in, such as alung
disease, you may produce more EPO to try to compensate for the low oxygen level.
•People who live at high altitudes may also have higher levels of EPO and so do chronic
tobacco smokers.

23. ERYTHROPOIETIN
•Ifyouproducetoomucherythropoietin,whichcanhappenwith
somebenignormalignantkidneytumorsandwithavarietyofothercancers,youmay
producetoomanyRBCs(polycythaemiaorerythrocytosis).
•Thiscanleadtoanincreaseintheblood'sthickness(viscosity)andsometimestohigh
bloodpressure(hypertension),bloodclots(thrombosis),heartattack,orstroke.