INSULIN-LIKE GROWTH FACTORS AND MUSCLE DIFFERENTIATION

Insulin-like growth factors I and II exert pleiotropic effects on diverse
cell types. Although current evidence supports a role for IGF-I as a major
postnatal growth factor, regulated in part by growth hormone, the functions
of IGF-II in growth and development remain undefined. Each IGF interacts
initially with a unique high-affinity receptor located in the plasma
membrane of responsive cells. Many of the actions of both peptides are
mediated by the IGF-I receptor, a ligand-activated tyrosine-specific
protein kinase structurally related to the insulin receptor. By contrast
the role of the IGF-II receptor in IGF signaling is unclear, despite its
apparent identity with the cation-independent mannose-6phosphate receptor
involved in targeting lysosomal enzymes. As an additional complexity
actions of both IGFs in target tissues may be modified by interaction with
various locally-secreted binding proteins. As part of a long-term goal to
define the mechanisms by which the actions of the IGFs are integrated
within the cell, the focus of this application will be on the functions and
regulation of IGF-II, the IGF-II receptor, and a novel IGF binding protein
in a model cell system, the differentiating myoblast. Toward this end the
following four specific aims are proposed: 1.To determine the role of IGF-II in muscle differentiation and to define
its mechanisms of qlction. 2.To dissect the functions of the IGF-II gene promoter, in order to define
and characterize the elements required for induction of gene expression
during myoblast differentiation. 3.To define the function of the IGF-II receptor in muscle differentiation
and to characterize the mechanisms involved in regulation of receptor gene
expression in this model system. 4.To determine the mechanisms of action and the regulation of a novel IGF
binding protein whose secretion is induced during myoblast differentiation.