Endocrine Abstracts

The IGF-I receptor (IGF-IR) growth/survival pathways are engaged in crosstalk with pathways induced by cell-cell interactions. Different elements of the IGF-IR signalling system also affect the phosphorylation status of molecules involved in the regulation of cadherin-mediated cell-cell adhesion, such as catenins. In addition, the IGF-IR has been shown to co-precipitate with cell adhesion complexes.

In this study, the crosstalk between IGF signalling and cell adhesion complexes in myogenesis was investigated. Myogenesis is the process in which proliferating muscle cells, known as myoblasts, differentiate into multinucleated myotubes. Multiple stimuli including growth factors (e.g. IGFs), the extracellular matrix, and direct cell-cell interaction co-ordinate the decision between proliferation verses differentiation.

The effect of cell density and application of exogenous IGF-II upon myogenesis was analysed in C2 myoblasts. In confluent cultures, the expression of Igf-2 was accelerated and increased by 2-fold compared to sub-confluent cultures. Moreover, abolishment of cell-cell contact by EGTA treatment caused a 4-fold reduction in Igf-2 expression and IGF-IR phosphorylation. In complementary experiments, exogenous IGF-II caused a 2-fold increase and acceleration of M-cadherin expression and earlier expression of N-cadherin in addition to the accelerated expression of myogenic markers (e.g., MHC, caveolin-3). This data suggests that IGF-II and cadherin-mediated adhesion function in a positive auto-regulatory loop with IGF-II promoting cadherin signalling and cell-adhesion promoting Igf-2 expression. Thus, IGF-II and cell-cell adhesion promote myogenic differentiation synergistically.

Future experiments will involve the specific blocking of cadherin-mediated adhesion and IGF-IR stimulation and study the effect upon cadherin expression, IGF signalling and myogenic signaling pathways. Results will provide novel insights into the connection of cadherin-mediated adhesion and IGF-IR stimulation and their downstream targets as well as their synergistic roles in the pathology of rhabdomyosarcoma, a common paediatric soft tissue sarcoma of skeletal muscle, in which both cadherins and IGF signalling has been shown to be abrogated.