Role of the microtubule destabilizing proteins SCG10 and stathmin in neuronal growth

Abstract

The related proteins SCG10 and stathmin are highly expressed in the developing nervous system. Recently it was discovered that they are potent microtubule destabilizing factors. While stathmin is expressed in a variety of cell types and shows a cytosolic distribution, SCG10 is neuron-specific and membrane-associated. It contains an N-terminal targeting sequence that mediates its transport to the growing tips of axons and dendrites. SCG10 accumulates in the central domain of the growth cone, a region that also contains highly dynamic microtubules. These dynamic microtubules are known to be important for growth cone advance and responses to guidance cues. Because overexpression of SCG10 strongly enhances neurite outgrowth, SCG10 appears to be an important factor for the dynamic assembly and disassembly of growth cone microtubules during axonal elongation. Phosphorylation negatively regulates the microtubule destabilizing activity of SCG10 and stathmin, suggesting that these proteins may link extracellular signals to the rearrangement of the neuronal cytoskeleton. A role for these proteins in axonal elongation is also supported by their growth-associated expression pattern in nervous system development as well as during neuronal regeneration.

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

“…Our results predicted that STMN1 is a potential miR-193b target, and in fact, this regulatory interaction was recently confirmed (Ikeda et al 2012). STMN1 is highly expressed in the developing nervous system and plays a role in axonal elongation and neuronal regeneration (Grenningloh et al 2004), and its overexpression was reported in malignant PCCs/PGLs (Bjorklund et al 2010). Although we observed an inverse correlation between miR-193b and STMN1 expression, it was not possible to assess a potential relationship between miR-193b, STMN1, and malignancy because our series lacked sufficient numbers of malignant tumors.…”

Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret

“…Tyrosine phosphorylation of Pcdhs by Ret may create binding sites for downstream effectors. Notably, we identified several proteins that copurify with Pcdhα4-TAP and are involved in neurite outgrowth and axonal pathfinding, such as stathmin-2, stathmin-3, and LAR (19,20). Furthermore, in yeast two-hybrid screens, Pcdhα was reported to bind to the cytoskeletal proteins neurofilament M and fascin and Pcdhγb1 was found to bind to stathmin-2 (reviewed in 16).…”

“…These Pcdh-interacting proteins include the receptor tyrosine kinase discoidin domain receptor 2 (DDR2), Ret, the receptor protein tyrosine phosphatase α (RPTPα), the leukocyte antigenrelated receptor tyrosine phosphatase (LAR), and several cell adhesion molecules that include the CD98 heavy chain and metadherin. Several of the interacting proteins are known to be involved in neurite outgrowth and axonal pathfinding, for example, the microtubule destabilizing proteins stathmin-like 2 and stathmin-like 3, LAR, and Ret (19)(20)(21).…”

Axon Formation in Neocortical Neurons Depends on Stage-Specific Regulation of Microtubule Stability by the Dual Leucine Zipper Kinase–c-Jun N-Terminal Kinase Pathway

“…Similarly, the efficiency of stage 2/stage 3 transitions was defined by the following formula: ST3/(ST2 ϩ ST3) ( A gross accumulation of stage 2 neurons was also observed after treatment with shRNA against the microtubule modulators, SCG10, DCX, and MAP2 (Fig. 8 A-C), which are thought to be physiological substrates for JNK (Chang et al, 2003;Gdalyahu et al, 2004;Grenningloh et al, 2004;Tararuk et al, 2006). As with DLK RNAi and JNK inhibitor treatment, RNAi directed against the microtubule-stabilizing proteins, DCX or MAP2, disrupted stage 2/stage 3 transitions of neuronal polarization, whereas its effect on stage 1/stage 2 transitions was relatively moderate (supplemental Table S1, available at www.jneurosci.org as supplemental material).…”

“…Microtubule regulators involved in axon formation, both in vivo and in vitro, include doublecortin (DCX), microtubule-associated protein 2 (MAP2), and superior cervical ganglion 10 (SCG10). These have been shown to be phosphorylated and to have their activity modulated by c-Jun N-terminal kinase (JNK) (Chang et al, 2003;Gdalyahu et al, 2004;Grenningloh et al, 2004;Tararuk et al, 2006). Therefore, the JNK pathway is a candidate signaling pathway that drives these microtubule regulators.…”