, 1998). The enhanced RhoA degradation may thus directly contributes to the accelerated neurite growth associated with axon formation. The absence of overt developmental defect in Smurf1 knockout mice suggests compensation by other molecules or pathways (Yamashita et al., 2005). Smurf2 represents one of the candidates that might be able to take the place of Smurf1 to regulate degradation of RhoA, when Smurf2 is relieved from the auto-inhibitory C2-HECT interaction (Wiesner et al., 2007). Unlike that found in Smurf1 or Smurf2 knockout mice, the Smurf1 and

Smurf2 double-knockout mice displayed planar cell polarity defects and severe abnormality of neural development, check details including the failure of neural tube closure (Narimatsu et al., 2009). Since these two ligases are not likely to share all of their targets, Smurf2 may act on another polarity-related protein that compensates Smurf1 deficiency, resulting in functional overlap in neuronal polarization between these two closely related Smurf proteins. Although early neural development defects prevented Fulvestrant in vitro the functional study of Smurfs in double-knockout mice, recent studies of

cultured hippocampal neurons suggests the involvement of Smurf2 in neuronal polarization through its interaction with polarity modulator Par3 and Rap1B (Schwamborn et al., 2007a and Schwamborn et al., 2007b). It remains unclear whether Smurf2 activity itself is regulated by polarizing factors during axon initiation and how Smurf1 and Smurf2 work in concert to properly regulate the degradation of their respective substrates. science The severe cell migration defect caused by Smurf1-shRNA alone (Figure S3B) is probably due to incomplete activation of compensatory mechanisms in transfected neurons and thus is unable to overcome the growth-inhibition effect of reduced Smurf1 expression. Importantly, we showed that Smurf1 regulation by BDNF and db-cAMP results in dual effects—it not only stabilizes a polarity-promoting protein Par6, but also selectively enhances the degradation of growth-inhibiting

RhoA. Thus, in addition to the enhanced stability of axon determinants, enhanced degradation of negative regulator(s) may also be important during axon formation. Furthermore, other substrates of Smurf1, such as talin head domain and hPEM-2 (a GEF for cdc42) and those involving in dynamic of focal adhesion (Huang et al., 2009 and Yamaguchi et al., 2008), could also contribute to axon formation regulated by Smurf1. Finally, we note that selective local protein degradation can also be achieved by modulating UPS components other than E3 ligase or by asymmetric distribution of proteasomes that are structurally and functionally heterogeneous, as shown in the liver cell (Palmer et al., 1996). Localized accumulation of axon determinants could also be achieved by asymmetric modulation of protein synthesis rather than protein degradation.