IGF-1Insulin-Like Growth Factor 1Matthew Klinka

BackgroundPrimarily produced in the liverHowever is also a paracrine

hormone◦Present in many cell types in a wide

range of tissue types.Typically bound to proteins when

both intra or extracellular◦98% of IGF-1 is protein bound◦IGFBP-3 most common

http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=20049

ProductionProduction of IGF-1 is linked to

dietary protein intake◦Especially casein◦Protein free diet can result in IGF-1

deficiencyMade in response to growth

hormone signalling

FunctionAnabolic Hormone

◦IGF-1 triggers growth until adulthood◦After adulthood triggers hypertrophy

in skeletal muscleRegulates kidney function and

growth

ReceptorReceptor is IGF1R

◦“Insulin-like growth factor 1 receptorTyrosine Kinase receptor

◦Dimeric◦Two sets of Alpha & Beta subunits◦320 Kda◦Member of the Insulin receptor

family◦Beta subunits contain the catalytic

tyrosine residues

IGF-2 BindingIGF1R may also bind IGF-2Key differences:

◦IGF-2 functions primarily in fetal development During gestation aids neural

development

◦IGF-1 functions in adults During gestation deals with physical

development

http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=68828

Primary ResultIGF1R triggering often results in

cell proliferation or growthHowever still a cell specific

response◦Ie: may trigger growth in size of an

adult’s skeletal muscle cells, or may trigger growth and subsequent division of embryonic cells

◦May even trigger growth (hypertrophy) of heart muscle cells

Role in reproductionIGF1R plays a role in the

development of limb buds in an embryo

IGF1R serves to facilitate lactation in pregnant and nursing females◦Differentiates breast cells into duct

and glandular tissue◦Prevents apoptosis of duct and

glandular tissue during pregnancy and nursing

CancerBecause of it’s anti-apoptotic

action, IGF1R may contribute to some cancers◦Prostate◦Breast◦Cervical

All of the above have been observed to contain cells with heightened levels of IGF1R

CraniosynostosisPremature ossification of sutures

in an infant cranium◦Results in oddly shaped skull and in

most cases brain damage if not corrected

Caused by a number of different single nucleotide polymorphisms in IGF1R

Secondary ReceptorIGF-1 Can also bind insulin

receptor◦Also a tyrosine Kinase receptor◦Much lower binding affinity than

IGF1R◦IGF-1 binds at 10% of the rate of

insulin◦May form a heterodimer with IGF1R

RegulationIn serum may be bound by

certain IGFBPs◦IGF-1 has a higher affinity for some

of these than it does for its receptor◦IGF1R may be targeted with tyrosine

kinase inhibitors◦miRNA thought to play a role in

regulation as well

Laron Syndrome

Laron SyndromeAutosomal recessiveResults from low levels or low

efficacy of IGF-1◦Most cases are due to a lack of GH

receptor◦Some due to mutation in genes

coding for IGF-1 or IGF1R

SymptomsNormal GH levelsVery low IGF-1 levelsShort statureProminent foreheadObesity in the trunk of the bodyLack of response to GH therapy

◦Typically used to treat other forms of dwarfism

TreatmentSynthetic IGF-1Must be taken before pubertyNot effective if there are other

mutations further along the signaling pathway

Cancer, Diabetes, and agingInterestingly, people with Laron

syndrome are nearly immune to cancer and diabetes.◦Two theories for cancer protection

1. IGF-1 has anti-apoptotic function Reduced IGF-1 results in more normal apoptosis

2. Lack of IGF-1 somehow results in more protection from oxidative DNA damage

Diabetes protectionLaron syndrome sufferers have

high insulin sensitivity despite being obese◦Most likely reason is because IGF-1

can bind insulin receptor◦In the absence of a competitor, a

smaller amount of insulin can have great effect

AgingIn mice, mutations reducing IGF-

1 levels resulted in longer lifespans on average◦In nematodes IGF-1 deficiency

resulted in doubling of lifespanMechanism is not understood

◦Unknown if this property occurs in humans Only ~300 people with Laron Syndrome

worldwide Difficult to establish a baseline because

incidence of accidental death is relatively common

http://www.biocarta.com/pathfiles/h_ghrelinPathway.asp

http://www.biocarta.com/pathfiles/h_igf1pathway.asp