Stathmin family phosphoproteins (stathmin, SCG10, SCLIP, and RB3/RB3/RB3؆) are involved in signal transduction and regulation of microtubule dynamics. With the exception of stathmin, they are expressed exclusively in the nervous system, where they display different spatio-temporal and functional regulations and hence play at least partially distinct and possibly complementary roles in relation to the control of development, plasticity, and neuronal activities. At the molecular level, each possesses a specific "stathmin-like domain" and, with the exception of stathmin, various combinations of N-terminal extensions involved in their association with intracellular membrane compartments. We show here that each stathmin-like domain also displays specific biochemical and tubulin interaction properties. They are all able to sequester two ␣ / tubulin heterodimers as revealed by their inhibitory action on tubulin polymerization and by gel filtration. However, they differ in the stabilities of the complexes formed as well as in their interaction kinetics with tubulin followed by surface plasmon resonance as follows: strong stability and slow kinetics for RB3; medium for SCG10, SCLIP, and stathmin; and weak stability and rapid kinetics for RB3. These results suggest that the fine-tuning of their stathmin-like domains contributes to the specific functional roles of stathmin family proteins in the regulation of microtubule dynamics within the various cell types and subcellular compartments of the developing or mature nervous system.
Stathmin, also referred to as Op18, is a ubiquitous cytosolic phosphoprotein, proposed to be a small regulatory protein and a relay integrating diverse intracellular signaling pathways involved in the control of cell proliferation, differentiation and activities. It interacts with several putative downstream target and/or partner proteins. One major action of stathmin is to interfere with microtubule dynamics, by inhibiting the formation of microtubules and/or favoring their depolymerization. Stathmin (S) interacts directly with soluble tubulin (T), which results in the formation of a T2S complex which sequesters free tubulin and therefore impedes microtubule formation. However, it has been also proposed that stathmin's action on microtubules might result from the direct promotion of catastrophes, which is still controversial. Phosphorylation of stathmin regulates its biological actions: it reduces its affinity for tubulin and hence its action on microtubule dynamics, which allows for example progression of cells through mitosis. Stathmin is also the generic element of a protein family including the neural proteins SCG10, SCLIP and RB3/RB3'/RB3". Interestingly, the stathmin-like domains of these proteins also possess a tubulin binding activity in vitro. In vivo, the transient expression of neural phosphoproteins of the stathmin family leads to their localization at Golgi membranes and, as previously described for stathmin and SCG10, to the depolymerization of interphasic microtubules. Altogether, the same mechanism for microtubule destabilization, that implies tubulin sequestration, is a common feature likely involved in the specific biological roles of each member of the stathmin family.
Stathmin is a ubiquitous phosphoprotein proposed to be a relay integrating various intracellular signaling pathways. Its high phylogenetic conservation and the identification of the related molecules, SCGIO in rat and XB3 in Xenopus, suggested the existence of a stathmin-related family. A systematic PCR-based approach allowed the identification of several novel mammalian sequences of which two coded for expressed members of the stathmin family; the translated RB3 sequence shares 88 % amino-acid identity with that of XB3 and is thus its rat homologue, and RB3' corresponds to an alternatively spliced product of the same gene, encoding a truncated form. Within their stathmin-like domain, the a helix, probably responsible for coiled-coil protein-protein interactions, is conserved, as well as are two consensus phosphorylation sites ; in their N-terminal extension domain, two cystein residues most likely responsible for membrane attachment through palmitoylation, are present in RB3/RB3' as in SCGIO. The novel identification and characterization of the corresponding proteins showed that all three are associated with the particulate, membrane-containing fraction. They furthermore display several spots of decreasing PI on two-dimensional immunoblots, suggesting that they are phosphorylated in uiuo. As for SCGIO, RB3 mRNA is detectable only in the nervous system by in situ hybridization, but at similar levels in the newborn and the adult brain as revealed by Northern blots, whereas SCGlO expression decreases in the adult. Furthermore, RB3 mRNA is undetectable in PC12 cells, whereas SCGlO mRNA increases after treatment with nerve growth factor, inducing neuronal differentiation. In conclusion, we demonstrate here the existence of a highly conserved stathmin-related family in mammals, of which each member seems to play specific roles, related to the control of cell proliferation and activities for stathmin and to that of neuronal differentiation for SCG10, the novel RBYRB3' proteins being rather related to the expression of differentiated neuronal functions. phosphorylation of its regulatory domain, conveying them to diverse target proteins 127, 331. In addition to its high molecular and biological conservation among vertebrates [4, 341, stathmin was identified as the generic element of a molecular family, of which two other members, SCGlO and XB3, have been identified previously. SCG10, which was first identified in rat as a marker of neuronal differentiation [35], contains a C-terminal stathmin-like domain and a specific N-terminal domain which might be responsible for the membrane association of SCGlO [36]. The other stathmin-related sequence was previously identified as the XB3 cDNA in Xencyus [34]. As SCGIO, the corresponding mRNA was detected exclusively in the nervous system, and its sequence revealed a similar structural organization of the corresponding protein. KeywordsThe existence of SCGIO and XB3 sequences containing a stathmin-like domain, as well as the previously recognized similar intron/exon structure of S...
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