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Insulin-like Growth Factor 1: “The Sulfation Factor”
Koray Kevin Celik
Endocrinology Seminar
Dr. David Champlin
Insulin-like growth factor 1 (IGF-1), also name Somatomedin C in the 1980’s, is a
protein hormone that in humans is encoded by the IGF1 gene. The growth factor was
initially identified in 1957 by Salmon and Daughaday, and was originally nominated as
the “Sulfation Factor” by the analog’s overall ability to stimulate 35-sulphate
incorporation into rat cartilage. IGF-1 is a hormone similar in molecular structure to
insulin. It plays an important role in childhood growth and continues to have
commanding anabolic effects in adults [3]. The growth factor and protein peptide consists
of 70 amino acids in a single chain with three intermolecular disulfide bridges, and has a
molecular weight of 7,649 Daltons.
Figure 1.0
Overall
there
are
three
major
observations
that
led
to
the
discovery
of
the
IGF/Somatomedin
family:
The
first
of
the
three
major
observations
occurred
early
in
1957
when
Salmon
and
Daughaday
first
witnessed
how
serum
stimulated
the
incorporation
of
35
S
into
incubated
cartilage.
The
serum
of
hypophysectomized
rats
lacked
the
sulfation
action
in
its
entirety.
Furthermore,
for
some
reason
it’s
activity
could
not
be
reconstituted
by
the
addition
of
further
quantities
of
growth
hormone
(GH)
to
the
maturation
medium,
but
rather
it
reappeared
after
further
administration
of
GH
to
hypophysectomized
rats
[1].
These
annotations
are
what
eventually
inspired
the
great
Daughaday
to
hypothesize
that
the
use
of
unaccompanied
recombinant
growth
hormone
does
not
actually
stimulate
growth
processes.
The
use
of
GH
satisfactorily
induces
the
formation
of
factors
that
mediate
the
message
of
growth
hormone
to
a
certain
degree.
These
unfathomable
factors
ultimately
lead
to
the
sulfation
of
cartilage
in
vitro,
which
reflects
growth
in
vivo.
The
second
of
the
three
major
observations
that
led
to
the
detection
of
IGF/Somatoden
C
originated
from
how
the
majority
cells
require
serum
to
grow
in
culture.
Several
growth
factors
in
serum
are
known
to
be
accountable
for
their
growth‐promoting
properties.
In
1972,
Pierson
and
Temin
extracted
factors
from
serum
in
which,
they
entitled
the
multiplication‐stimulating
activity
(MSA).
These
factors
had
molecular
weights
just
below
10,000
Dalton’s
and
were
subject
to
stimulate
cells
to
replicate
when
added
to
a
culture
medium.
Subsequently,
they
hypothesized
and
confirmed
that
cultured
liver
cells
did
indeed
secrete
MSA
into
the
culture
medium(s)
[2].
This
demonstration
was
the
first
of
its
kind,
where
we’d
seen
the
likes
of
MSA
being
produced
primarily
in
the
liver
and
that
MSA
may
eventually
lead
to
autocrine
stimulation
via
the
same
cells
by
which
it
was
initially
secreted.
The
third
most
imperative
observation
that
led
to
the
discovery
of
insulin‐
like
growth
factors
stemmed
from
a
vastly
different
series
of
observations.
It
was
noted
in
great
detail
that
serum
employs
insulin‐like
effects
on
insulin
target
tissues
such
as
muscle
and
adipose
tissue.
The
effects
of
insulin
on
serum
initially
were
not
suppressed
by
the
addition
of
anti‐insulin
serum,
and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s
[3].
The
molecules
found
in
serum
evidently
are
responsible
for
the
insulin‐like
effects
that
were
investigated
for
and
were
finally
identified
as
insulin‐like
growth
factors
I
and
II
[4].
Additionally there is a synthetic analog of IGF-1, known as Mecasermin, IGF-1
LR3 (long recombinant receptor grade 3) that is sold legally under the trade name
Increlex. The LR3 is a long-term analog of human IGF-1, specifically designed and
manufactured for mammalian cell culture to support large-scale manufacturing of
recombinant biopharmaceuticals. Recombinant Human LR3 IGF-1 is a single, nonglycosylated polypeptide chain containing 83 amino acids, which encompass the
complete human IGF-1 sequence with the substitution of an Arganine (R) for the
Glutamic Acid (E) at position three, consequently R3, and a 13 amino acid extension
peptide at the N terminus. This sequence alteration allows the recombinant hormone to
circumvent binding proteins as well as to increase its respective half-life within the blood.
R3 IGF-1 has been produced with the purpose of increasing biological activity and is
significantly more potent than human IGF-I in vitro. The growth factor is currently being
used for the treatment of growth failure and severe burns. It has a Chinese counterpart
that is often replicated and seen being sold and abused in great numbers within the
contexts of bodybuilding and professional sports.
Figure 2.0
Within the black market paradigm there are two types made commonly available,
Media and Receptor grades, respectively which ascertain predominantly to their overall
quality. The synthetic analogue is seen as a principal hormonal mediator of statural
growth. Under normal circumstances, after subcutaneous or intra-muscular injection,
growth hormone (GH) binds to its respective receptor in the liver, as well as in several
other tissues, and stimulates the synthesis and secretion of IGF-1. In target tissues, the
Type 1 IGF receptor, which is homologous to the insulin receptor, which is activated by
IGF-1, leading to intracellular signaling which agonizes multiple processes leading to
statural growth, hyperplasia and mitogenensis. The metabolic actions of IGF-1 are in
great detail directed at encouraging the overall uptake of glucose, fatty acids, and amino
acids so that metabolism supports growing tissues.
Figure 3.0
As seen in the image above, the diagram depicts circulating IGF-1 levels in the
blood and in tissue. The majority of circulating IGF-1 is credited being produced in the
liver. Hepatic IGF-1 production is subject to complex regulation by both hormonal and
nutritional factors. Various IGF-binding proteins (IGFBP’s) are also produced in the
liver. In IGF-responsive tissues, the ligands IGF1 and IGF2 as well as IGFBPs can be
delivered through the circulation from the liver, but IGFs and IGFBPs can also be
produced locally through autocrine or paracrine mechanisms [5]. These mechanisms
habitually comprise interactions between stromal- and epithelial-cell subpopulations.
Furthermore, Growth hormone is predominantly produced in the pituitary gland under the
mechanism of the hypothalamic factors growth-hormone-releasing hormone (GHRH)
with Somatostatin (SMS) acting as the major stimulator of IGF-1 production [6].
Figure 4.0
(Above) IGF-1 and its receptor IGF-1R come together to undertake a resilient
proliferative signaling system. This system when agonized correctly stimulates the likes
various forms of mitogenensis and halts the cell signal known as apoptosis (cell suicide).
In real life situations IGF-1 acts as a precursor for countless bodily growth hormone
responses, many are still being discovered today. One of the main components of the
IGF-1 mitogenic signaling factor is the association of the receptor tyrosine kinase with
Shc, Grb2, and Sos-1 to activate ras and the Map kinase cascade (raf, Mek, Erk) [6]. The
culmination of the signaling pathways is seen at the end of the Map kinase pathway,
which, is a modification of specific transcription factor activity, such as activation of
ELK transcription factors. Serum response factor (SRF) and AP-1 contribute to mitogenic
signaling by many factors. Phosphorylation of IRS-1 and PI3 kinase activation are also
involved in IGF-1 signaling, similar to insulin signaling.
Figure 5.0
As previously discussed the IGF-1 receptor is a tyrosine kinase cell-surface
receptor that binds to either IGF1 or IGF2. Above we see the respective receptor(s) being
triggered by IGF-1 both at the target site(s) as well as downstream.
IGF-binding proteins and IGFBP proteases have significant roles in regulating
ligand bioavailability. Ligands are delivered either from remote sites of production
through the circulation or are locally produced. There is strong evidence that certain
IGFBPs also have direct growth-regulatory actions that can stimulate beneficial
mitogenensis as well as stimulate the growth of proto-oncogenes. The local
bioavailability of ligands is subject to complex physiological regulation and is
abnormally high in most cancers. IGF-binding proteins chef responsibilities include
prolonging the half-life of the IGFs, as well as having a strong affinity for IGFs
comparable to IGF1R. Moreover, it is noted that there is fierce competition between
IGFBPs and IGF1R for the available ligands in tissue and in blood [5]. This potential for
competition leads to the latter effect of increasing IGF1R activation. Further, The IGF2R
binds to IGF2, but has no tyrosine kinase domain and appears to act as a negative
influence on proliferation by reducing the amount of IGF2 available for binding to
IGF1R. Certain IGFBP proteases, which are more often than not produced by neoplastic
cells, cleave IGFBPs and can discharge free ligand and thereby increase IGF1R
activation [6]. Subsequently, ligand binding to IGF1R, its tyrosine kinase action is
activated, which further agonizes the signaling pathway through intracellular networks
that control cell proliferation and cell survival.
Key downstream networks include the PI3K-AKT-TOR system and the RAFMAPK systems. Activation of these pathways stimulates proliferation and inhibits
apoptosis, and stimulates the TOR, target of rapamycin. Such mutations have been shown
to inhibit key molecules involved in insulin signaling (IIS) and the nutrient signaling
pathway Target of Rapamycin (TOR). These mutations in TOR (in this case RSKS-1)
result in a 30 percent lifespan extension, while mutations in IIS (Daf-2) often result in a
doubling of lifespan in the worms [7].
References
[1] Binoux, M., R Hossenlopp, C. Lassarre and D. Seurin. 1980. Somatomedin
production by rat liver in organ culture. I. Validity of the technique.
Influence of the released material on cartilage sulphation. Effects of growth
hormone and insulin. Acta Endocrinol. 93:73.
[2] Dulak, N. and H. J. Temin. 1973. A partially purified polypeptide fraction from rat
liver cell conditioned medium with multiplication stimulating activity for
embryo fibroblasts. J. Cell. Physiol. 81:153.
[3] Froesch, E. R., MD, Ch Scmid, PHD, I. Zangger, MD, and E. Eigenmann. "Journal of
Clinical Investigation." Editorial. EFFECTS OF IGF/SOMATOMEDINS
ON GROWTH AND DIFFERENTIATION OF MUSCLE AND BONE Jan.
1986: 57-75. Print.
[4] Rinderknecht, E. and R. E. Humbel. 1978a. The amino acid sequence of human
insulin-like growth factor I and its structural homology with proinsulin. J.
Biol. Chem. 253:2769.
[5] Perrini,, Sebastio, Luigi Laviola, Marcos C. Carreira, Angello Cignarelli, Annalisa
Natalicchio, and Francesco Giorgino. "The GH/IGF1 Axis and Signaling
Pathways in the Muscle and Bone: Mechanisms Underlying Age-related
Skeletal Muscle Wasting and Osteoporosis." Journal of Endocrinology review (n.d.): 201-10. 2011. Web. 04 Mar. 2014
[6] "IGF-1 Technical Mode of Action on Proliferation and Neoplasia- Everything You
Need to Know." Peptide Resource All About Peptides. Purepeptide.com,
2011. Web. 04 Mar. 2014.
[7] Pankaj Kapahi, PhD et al. Germline Signaling Mediates the Synergistically
Prolonged Longevity by Double Mutations in daf-2 and rsks-1 in C. elegans. Cell
Reports, December 2013