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been shown to be a target of Sema3A in triggering growth cone collapse of
sensory neurons (
Chadborn et al., 2006
). Sema3A induces a rapid local
accumulation of PTEN at the growth cone, possibly leading to a depletion
of PIP3 and AKT (
Chadborn et al., 2006
).Thus,inadditiontotheRho/
ROCK cascade, PTEN seems to be another signal transduction pathway
that is activated by inhibitors of axon growth.
3. SOCS3: AN INHIBITOR OF CYTOKINE-INDUCED AXON
REGENERATION
Several recent studies have indicated that SOCS3 is another neuron-
intrinsic blocker of axon regeneration. It is one of the most highly
upregulated genes in neurons following axonal injury (
Fischer, Petkova,
Thanos, & Benowitz, 2004; Veldman, Bemben, Thompson, & Goldman,
2007
). Over 30 cytokines, including CNTF, leukemia inhibitory factor
(LIF), interleukin-6 (IL6), IL10, and interferon (IFN)-gamma are known
inducers of SOCS expression (
Croker, Kiu, & Nicholson, 2008;
Lehmann et al., 2003; Park et al., 2009; Strebovsky, Walker, & Dalpke,
2012
). Cytokine binding to a cognate receptor leads to activation of the
JAK ( Janus kinase)/STAT pathway and induction of
Socs
gene
transcription in a STAT-dependent manner (
Cooney, 2002; Croker
et al., 2008
). The SOCS proteins then inhibit cytokine signaling either
by direct binding to JAKs and inhibiting their catalytic activity or by
binding to the receptor site and preventing recruitment of STAT.
Alternatively, SOCS proteins interact with the cellular ubiquitination
machinery and direct JAKs or receptors for ubiquitin-mediated
proteasomal degradation (
Fig. 7.2
)(
Alexander & Hilton, 2004; Cooney,
2002
). Through this negative feedback system, the SOCS family is able
to tightly regulate the intensity and duration of cytokine signaling, which
is critical to prevent aberrant cellular responses in the event of sudden
increases in cytokine concentration. Of the different SOCS members,
SOCS3, which has been shown to be expressed in immune cells and play
prominent roles in modulating immune reactions (
Baker, Akhtar, &
Benveniste, 2009; Li, de Haar, Peppelenbosch, & van der Woude, 2012;
Tamiya, Kashiwagi, Takahashi, Yasukawa, & Yoshimura, 2011
) has
attracted considerable attention recently for its prominent role in limiting
cytokine-mediated axon regeneration. One of the early evidence
indicating a direct role for SOCS3 in limiting axon regeneration showed
that overexpression of SOCS3 blocks nuclear translocation of STAT3
