Mature mouse IGF-1 is a non-glycosylated, 70 amino acid (aa)
secreted polypeptide that is derived from either a 153 aa or a 159 aa
preproprotein. It shares 99% and 94% aa sequence identity with rat and human
IGF-1, respectively. IGF-1 is synthesized in the liver and other tissues. It is
found in blood and other body fluids as a complex with specific high affinity
IGF binding proteins (IGFBP-1 to -6). The IGFBPs are expressed in specific
patterns during development. They are modulators of IGF actions, which control
IGF bioavailability to specific cell-surface receptors. Their functions are
further regulated by IGFBP proteases, which proteolytically cleave the IGFBPs
to lower the affinity with which they bind IGFs and increase IGF
bioavailability. Some IGFBPs also have IGF-Independent effects on cell
functions. IGF-Independent circulates primarily as a ternary complex with
IGFBP-3 or IGFBP-5 and the acid-labile subunit (ALS). Some IGF-1 is also
present in binary complexes with other IGFBPs. Whereas the ternary complexes
are generally restricted to the vasculature, the binary complexes freely enter
the tissues.
IGF-1 actions are mediated by two ubiquitously expressed
receptor tyrosine kinases: IGF-I R and Insulin R/CD220. IGF-I R and Insulin R
are disulfide-linked heterotetrameric complexes that consist of two alpha and
two beta subunits. For both of these receptors, the prepro proteins are cleaved
to produce extracellular alpha subunits which contain a cysteine-rich region
and ligand-binding fibronectin type III (FN-III) domains, and beta subunits
which contain an extracellular FN-III domain, transmembrane, and cytoplasmic
tyrosine kinase domains. A hybrid complex containing one IGF-I R and one
Insulin R also serves as a functional high affinity receptor for IGF-1. IGF-I
R-Insulin R hybrids respond primarily to IGF-1, potentially downregulating the
cellular response to Insulin. IGF signaling is also modulated by IGF binding
proteins and the scavenger receptor, IGF-I I R.
Powered by Bioz
