Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth

Abstract

In the developing nervous system, Id2 (inhibitor of DNA binding 2, also known as inhibitor of differentiation 2) enhances cell proliferation, promotes tumour progression and inhibits the activity of neurogenic basic helix-loop-helix (bHLH) transcription factors. The anaphase promoting complex/cyclosome and its activator Cdh1 (APC/C(Cdh1)) restrains axonal growth but the targets of APC/C(Cdh1) in neurons are unknown. Id2 and other members of the Id family are very unstable proteins that are eliminated as cells enter the quiescent state, but how they are targeted for degradation has remained elusive. Here we show that Id2 interacts with the core subunits of APC/C and Cdh1 in primary neurons. APC/C(Cdh1) targets Id2 for degradation through a destruction box motif (D box) that is conserved in Id1 and Id4. Depletion of Cdh1 stabilizes Id proteins in neurons, whereas Id2 D-box mutants are impaired for Cdh1 binding and remain stable in cells that exit from the cell cycle and contain active APC/C(Cdh1). Mutants of the Id2 D box enhance axonal growth in cerebellar granule neurons in vitro and in the context of the cerebellar cortex, and overcome the myelin inhibitory signals for growth. Conversely, activation of bHLH transcription factors induces a cluster of genes with potent axonal inhibitory functions including the gene coding for the Nogo receptor, a key transducer of myelin inhibition. Degradation of Id2 in neurons permits the accumulation of the Nogo receptor, thereby linking APC/C(Cdh1) activity with bHLH target genes for the inhibition of axonal growth. These findings indicate that deregulated Id activity might be useful to reprogramme quiescent neurons into the axonal growth mode.

Id2 gene-targeted crosstalk between Wnt and retinoid signaling regulates proliferation in human keratinocytes

“…In a different experimental system, glucocorticoid-induced decline in proliferation of neural stem cells was abrogated in the presence of 0.5 mM of a potent proteasomal inhibitor MG132, reflecting an involvement of the ubiquitin proteasomal pathway (Sundberg et al, 2006). Furthermore, Id2 has been identified as a potential substrate for some E3 ubiquitin ligase complexes and, thus, can be targeted for proteasomal degradation (Lasorella et al, 2006). Therefore, we investigated whether MG132 would be able to counteract the antiproliferative action of atRA in HaCaT cells.…”

Interference of the dominant negative helix–loop–helix protein ID1 with the proteasomal subunit S5A causes centrosomal abnormalities

“…Stability of all ID proteins appears to be regulated by the ubiquitin proteasome system (Anand et al, 1997;Bounpheng et al, 1999;Fajerman et al, 2004;Lasorella et al, 2006). Indeed, ID proteins can bind different components of , 1997), and ID1 and ID3 bind to the JAB1 protein, a subunit of the COP9 signalosome (Bounpheng et al, 1999;Berse et al, 2004;Trausch-Azar et al, 2004).…”

“…This phosphorylation event may trigger their ubiquitin-mediated proteasomal degradation and/or alter their protein-binding specificities (Deed et al, 1997;Bounpheng et al, 1999). All ID proteins but ID3 contain a destruction box (D box), a recognition sequence for the anaphase-promoting complex (APC/ C) (Lasorella et al, 2006), targeting them for ubiquitinmediated proteasomal degradation. In addition, ID1 can interact with the 26S proteasome subunit S5A/ Rpn10 (Anand et al, 1997).…”

Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1

“…Degradation of Six1 by the APC is notable, as currently only two other transcription factors, HOXC10 (Gabellini et al, 2003) and Id2 (Lasorella et al, 2006), have been identified as APC targets. Like Six1, Id2 is a developmentally important transcription factor that affects cellular proliferation and tumor progression (Lasorella et al, 2001).…”