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Microtubule Dynamics: If You Need a Shrink Try Stathmin/Op18 Sean Lawler

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Microtubule Dynamics: If You Need a Shrink Try Stathmin/Op18 Sean Lawler View metadata, citation and similar papers at core.ac.uk brought to you by CORE R212 Dispatch provided by Elsevier - Publisher Connector Microtubule dynamics: If you need a shrink try stathmin/Op18 Sean Lawler Recent studies show that stathmin/Op18 may be an kinase A (PKA), and Ser16 by the Ca2+/calmodulin- important physiological regulator of microtubule dependent kinase-Gr (CaMK IV/Gr). There are almost dynamics; the activity of stathmin/Op18 is controlled by certainly additional unidentified kinases which phospho- the actions of several signalling pathways, allowing it to rylate stathmin/Op18. play a central role in coordinating microtubule behaviour. Modulation of stathmin/Op18 levels by overexpression or Address: MRC Protein Phosphorylation Unit, Department of Biochemistry, Dundee University, DD1 4HN, UK. with anti-sense cDNAs results in a striking cell-cycle block at the G2/M transition, suggesting an involvement Current Biology 1998, 8:R212–R214 in cell-cycle progression [5]. The function of http://biomednet.com/elecref/09609822008R0212 stathmin/Op18 remained elusive, however, until the © Current Biology Ltd ISSN 0960-9822 protein was purified in a screen for factors that could inhibit microtubule polymerisation [6]. This showed that, The regulation of microtubule dynamics in eukaryotic in vitro, stathmin/Op18 interacts with unpolymerised cells is essential for a multitude of processes, such as cell tubulin and destabilises microtubules, and conversely that movement, morphology, division and cytoplasmic its depletion from Xenopus egg extracts increases micro- organisation [1]. Microtubules are dynamic polymers of αβ tubule formation. These effects were attributed to an tubulin dimers, the behaviour of which is determined by a increased microtubule catastrophe rate, and may underlie combination of the rates of growth, shrinkage, rescue the previously observed cell-cycle blockade by stath- (change from a shrinking to a growing state) and min/Op18. These observations were a major breakthrough catastrophe (change from a growing to a shrinking state). in stathmin/Op18 research, and rapid progress has since This probably involves the coordinated action of several been made which has shown that stathmin/Op18 is a phos- proteins, but few have been identified and their mode of phorylation-controlled general physiological regulator of action is unclear [2]. The protein stathmin/Op18, microtubule dynamics. however, has recently emerged as a potentially crucial regulator of microtubule dynamics. Phosphorylation and microtubule destabilisation It is now well established that stathmin/Op18 inhibits micro- Stathmin/Op18 — a brief history tubule polymerisation and also depolymerises microtubules Stathmin/Op18 is a 19 kDa cytoplasmic protein that has in a dose-dependent fashion; importantly, this has been been independently isolated by a number of investigators demonstrated in living cells [7,8]. Furthermore, phosphory- in the past few years [3–5]. Various observations indicated lation of stathmin/Op18 on all four sites completely blocks that stathmin/Op18 plays an important role in cell its microtubule-destabilising effect [9]. Thus, unphosphory- regulation. The protein is well conserved and highly lated stathmin/Op18 promotes microtubule disassembly, expressed in proliferating cells and neurons. Its expression and this activity is turned off by phosphorylation. level changes markedly during development, cellular dif- ferentiation and tissue regeneration, and is elevated in Overexpression of mutant forms of stathmin/Op18 in some neoplastic cells. Particularly notable are the diverse which the phosphorylation sites are replaced by alanines phosphoforms of stathmin/Op18 which have been causes a major G2/M block [4] and destabilises micro- observed, the result of phosphorylation on four serine tubules [7,8]. Interestingly, wild-type stathmin/Op18 also residues that is stimulated by a wide range of extracellular destabilises interphase microtubules, but the cells effectors and during mitosis. progress apparently normally through the cell cycle. This difference occurs because the elevated kinase levels that Stathmin/Op18 consists of a carboxy-terminal α-helical occur during mitosis are enough to phosphorylate and domain and an amino-terminal ‘regulatory’ domain that thereby inactivate the overexpressed wild-type protein, contains the four serine phosphorylation sites (residues 16, whereas the alanine mutants cannot be phosphorylated 25, 38 and 63) that account for all the phosphoforms and are constitutively active [7]. Phosphorylation- observed [3]. These sites are the targets of multiple mediated down regulation of stathmin/Op18 activity is kinases regulated both during the cell cycle and by signal thus required for progression through mitosis. transduction cascades. Ser25 is a target for mitogen-acti- vated protein (MAP) kinase, and both Ser25 and Ser38 are Experiments using in vitro phosphorylated stathmin/Op18 targets for phosphorylation by cyclin-dependent kinases or mutated forms have shown that its regulation may be (Cdks). Ser16 and Ser63 can be phosphorylated by protein quite complex [9] (see Table 1). It appears that Ser16 and Dispatch R213 Ser63 make the greatest contribution to stathmin/Op18 Table 1 inactivation, a single aspartic acid substitution at Ser63 Stathmin/Op18 phosphorylation effects on microtubule stability. being sufficient to block the microtubule depolymerisa- tion effect in microinjected cells [8]. Phosphorylation of Microtubule both Ser16 and Ser63 has a greater effect on microtubule Sites phosphorylated destabilisation stability in vitro than that of either site alone, suggesting 16 25 38 63 an element of cooperativity. In contrast, phosphorylation of Ser25 and Ser38 has little effect on microtubules in – – – – + + + + vitro. Indeed, overexpression of the Ala16/Ala63 mutant – P P – + + + has a strong destabilising effect on microtubules, despite P––– + + being efficiently phosphorylated at both Ser25 and Ser38 – – – P + + by mitotic kinases [9]. PP P – + –PPP +/– A clue to the function of Ser25 and Ser38 phosphorylation P– – P – comes from overexpression of Ala25/Ala38 mutant stath- PPPP – min/Op18, which gives a strong cell-cycle block, and Stathmin/Op18 was phosphorylated in vitro on the sites marked, and causes microtubule depolymerisation [7]. It turns out that, the effects on microtubule polymerisation were observed in an in vitro in this mutant, Ser16 and Ser63 do not become phospho- assay (from [9]). rylated, probably accounting for its effects, and indicating a necessity for ordered phosphorylation in stathmin/Op18 that stathmin/Op18 causes spindle disassembly in vitro inactivation. Thus, Ser16 and Ser63 regulate microtubule [6,14] and that, in cells expressing alanine mutants of destabilisation, and phosphorylation of Ser25/Ser38 is stathmin/Op18, the spindle does not form or has abnor- required for Ser16/Ser63 phosphorylation, at least during mally short arms [7,9]. The microtubule-destabilising mitosis. All the sites can be phosphorylated efficiently in effect of these mutant proteins thus appears to prevent vitro, so it may be in the tubulin-bound form that sequen- proper spindle formation. Two recent studies using tial phosphorylation is required for stathmin/Op18 inacti- Xenopus egg extracts support a role for stathmin/Op18 in vation, Ser25 and/or Ser38 phosphorylation allowing spindle formation [13,14]. Inhibition of protein phos- access to the other two sites. phatase 2A (PP2A) by okadaic acid was found to cause excessive spindle microtubule growth in extracts, which Stathmin/Op18 interacts directly with αβ tubulin dimers correlated with a decreased catastrophe frequency and [6,9,10,11], and no interaction has been observed between could be rescued by the addition of a constitutively-active stathmin/Op18 and microtubules. A 217 kDa complex stathmin/Op18 mutant [13]. The catastrophe frequency consisting of two tubulin heterodimers per stathmin/Op18 also decreased on immunodepletion of stathmin/Op18 molecule was observed [10,11], and the interaction from the extracts, suggesting that stathmin/Op18 may be a appears to occur primarily between stathmin/Op18 and α- substrate of PP2A in microtubule regulation, mediating at tubulin [9]. The region of stathmin/Op18 necessary for least some of its effects on microtubule stability [13]. microtubule interaction has not been determined, but deletion of the amino-terminal 54 amino acids destroys its Stathmin/Op18 is known to be highly phosphorylated in ability to depolymerise microtubules [7]. mitosis, so it was surprising that its phosphorylation was at a similar low level in both mitotic and interphase Xenopus Whether stathmin/Op18 is truly a microtubule catastrophe egg extracts [14]. However, the addition of increasing factor, as originally proposed [6], is still not clear. Some amounts of mitotic chromatin to the mitotic extract caused studies have found a correlation between stathmin/Op18 a dose-dependent increase in stathmin/Op18 phosphoryla- and catastrophe frequency [12,13], but others have not tion. Mitotic chromatin thus contains an activity that can [10]. Stathmin/Op18 could simply sequester αβ tubulin render a mitotic extract capable of hyperphosphorylating dimers and thereby alter the equilibrium conditions to stathmin/Op18. Inhibition of PP2A in the mitotic extract favour depolymerisation of microtubules, small changes could mimic these effects, so mitotic chromatin may being sufficient to cause a rapid microtubule depolymeri- contain a
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