SH2B1ß regulates N-cadherin levels, cell-cell adhesion and nerve growth factor-induced neurite initiation.

ABSTRACT

Little is known regarding the role of inter-cellular interaction during neuronal differentiation. Homophilic N-cadherin engagement between cells contributes to neuronal migration. However, its function in neurite initiation is not clear. In this study, we provide the first evidence that the adaptor protein SH2B1ß regulated N-cadherin levels and neurite initiation. Overexpression of SH2B1ß reduces N-cadherin levels and increased phosphotyrosine 654 ß-catenin, leading to increased nerve growth factor-induced neurite initiation in PC12 cells, an established model for neuronal differentiation. In contrast, overexpression of the dominant-negative mutant SH2B1ß(R555E) increases N-cadherin expression, cell-cell aggregation, and reduces neurite initiation. Moreover, SH2B1ß binds directly or indirectly to N-cadherin indicative of its involvement in regulating the levels of N-cadherin. Taken together, these findings provide significant new insights into how N-cadherin-mediated inter-cellular interactions may influence neurite initiation and how SH2B1ß may regulate these processes.