The recruitment of SHP2 to ephrin-A1
6XHis EphA2 is followed by the dephosphorylation of focal adhesion kinase and paxillin [11]. Barberis et al. demonstrated that Sema4D-stimulation leads to the dephosphorylation of focal adhesion kinase in Plexin-B1 expressing NIH3T3 fibroblasts [9]. It is thus likely that focal adhesion kinase is one of the substrates of SHP2 in Sema4D-signaling. This dephosphorylation may bring the inactivation of integrin-mediated cell adhesion, cell rounding and/or the growth cone collapse response. The contribution of SHP2 to repulsive response could also be explained by the regulation of small G-protein RhoA [22]. It has been shown that SHP2 dephosphorylates and inactivates p190B-RhoGAP [23]. Since Sema4D activates RhoA through the interaction of Plexin-B1 and Rho-GEFs [1] and [5], SHP2-mediated inactivation of p190B-RhoGAP may also augment the activation of RhoA, which leads to the reorganization of cytoskeleton in the neurons. Alternatively, Sema4D-activated SHP2 may dephosphorylate Rho-kinase II to induce deadhesion of growth cones as suggested in non-neuronal
cells [24]. Identification of neuronal substrates of SHP2 in Sema4D-repulsive signaling will provide new insights into the molecular mechanism of axon guidance.
