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2603-2606-Vimentin and Post-Translational Modifications In European Review for Medical and Pharmacological Sciences 2016; 20: 2603-2606 Vimentin and post-translational modifications in cell motility during cancer – a review A.-M. SHI1, Z.-Q. TAO2, R. LI3, Y.-Q. WANG4, X. WANG5, J. ZHAO6 1School of Public Health of Nanjing Medical University, Nanjing, China 2Department of Science and Education, Xuzhou Central Hospital, Xuzhou, China 3Central laboratory, Xuzhou Central Hospital, Xuzhou, China 4Department of Oncology Surgery, Xuzhou Central Hospital, Xuzhou, Jiangsu, China 5Department of Thoracic surgery, Xuzhou Central Hospital, Xuzhou, Jiangsu, China 6Department of Science and Education Division, Xuzhou Central Hospital, Xuzhou, China Abstract. – The post-translational modifica- of the phosphate group. Of note, kinases make tions (PTMs) are defined as the covalent mod- up around 2% of the genome3, whereas there are ification or enzymatic modification of pro- approximately 50% phosphatases which in turn teins during or after protein biosynthesis. implies that phosphatases are less specific than Proteins are synthesized by ribosomes translat- 4 ing mRNA into polypeptide chains, which may kinases . Sequential protein phosphorylation then undergo PTM to form the mature protein events can act as a form of signal amplification. product. PTMs are important components in Co-operative phosphorylation events require cell signaling. Moreover, it is a known fact that several phosphosites that are usually modified PTM regulation offers an immense array and before a signal is generated. Each of these types depth of regulatory possibilities. The present of multi-phosphorylation events can be consid- review article will focus on their possible role in cancer cell motility with special reference to ered as a threshold to regulate filament organi- vimentin, an intermediate filament (IF), as the zation or cell signaling events. While much of later is an important process responsible for the focus on the next couple of sections is on the life-threatening state viz. cancer metastasis. action of phosphorylation and kinases, dephos- phorylation by phosphatases is also equally im- Key Words: Post-translational modifications, Inter- mediate filaments, Cancer, Metastasis, Vimentin. portant to maintain phosphoprotein homeostasis since hyperphosphorylation of IFs is a trigger for many diseases including cancer. Introduction Overview of Intermediate Filament Intermediate filaments (IFs) are regulated at Phosphorylation transcriptional, translational and post-translational IF phosphorylation as a regulator of IF organi- levels1. The prime focus of the present report is on zation and function is implicated in a whole host the regulation of IFs either by their posttranslational of cellular processes and pathologies5. Phosphor- modifications (PTM) or by their assembly. PTMs ylation of IFs typically occurs on the head and are one of the key regulators of IF function. The tail domains. Phosphosites have been predicted combination of allosteric and orthosteric PTM by mass spectrometry (MS) on the central heli- regulation combined with the fact that many cal rod domains, although these are unvalidated6. PTMs cross-talk, provides an array of regulatory Phosphorylation is a transient PTM that regulates possibilities. This has been referred to as the “PTM the dynamic assembly and disassembly of IF fil- code” that actually infers how proteins regulate a aments7. Often the protein aggregation is a mis- diverse range of biological functions2. regulation of phosphorylation processes, which The PTM namely eukaryotic phosphorylation can result in the diseased state. As such, control involves the addition of a phosphate group to of phosphorylation needs to be tightly regulat- a serine (S), threonine (T) or tyrosine (Y) res- ed to preserve cellular and tissue homeostasis. idues on a protein. It is catalyzed by a kinase, The roles of phosphorylation in IF regulation are while protein phosphatases catalyze the removal three-fold viz. IF assembly, protein-protein inter- Corresponding Author: Ziqi Tao, MD; e-mail: [email protected] 2603 A.-M. Shi, Z.-Q. Tao, R. Li, Y.-Q. Wang, X. Wang, J. Zhao actions and signaling; however, they are all inter- sion, locomotion of the cell body and retraction connected. Phosphorylation on the vimentin head of the trailing edge. Activation of two key effec- domains disrupts IF dimerization8 and it reduces tors of migration, cell division control protein 42 the affinity of IF head domains for the central rod homolog (Cdc42) and Ras-related C3 botulinum domains, thus promoting disassembly9. The in- toxin substrate 1 (Rac1) causes tyrosine phos- fluence of phosphorylation is more complex, as it phorylation-dependent collapse of the vimentin can also induce structural changes in the non-ad- network13. Furthermore, nothing is known about jacent linker 2 and C-terminus10. In the context of the specific sites of vimentin tyrosine phosphor- the discussion above, this type of phosphorylation ylation; it has merely been reported to exist in a event would be considered allosteric. It must be few studies, several of which connect it to the ac- stressed that most of these structural studies have tivity of the migration effector PI3K14. PI3Kγ-de- been conducted in in vitro systems and may not pendent phosphorylation of vimentin on serines mimic the reality of in vivo vimentin assembly/ namely S6 and S38, induces vimentin filament disassembly. Examples of the other roles of phos- reassembly and retraction from the cell periphery. phorylation as a regulator of protein-protein inter- In particular, inhibition of the phosphorylation of actions and signaling will be covered in the next S6 and the adjacent serines impaired transendo- section with a particular focus on vimentin. thelial migration, demonstrating that disassembly of the vimentin network is important for proper Vimentin Phosphorylation cell motility. Since PI3K does not directly phos- Vimentin has 23 identified phosphorylation sites phorylate vimentin, it could act upstream through on its N-terminus and C-terminus11. The N-termi- several effectors to induce vimentin phosphor- nus phosphosites are primarily regarded to regulate ylation, such as Rac, or Akt. Akt1 is a known vimentin organization and protein-protein interac- scaffolding target of vimentin; it phosphorylates tions. In particular, it seems that certain phospho- vimentin at S38, and facilitates cell migration. sites are specifically phosphorylated by one or two Inhibition of PI3K prevented the Akt1 phosphor- kinases. On the other hand phosphosite such as S38, ylation of vimentin thereby, confirming PI3K ki- observed to be commonly phosphorylated by a large nase as an upstream activator of Akt induced vi- set of kinases, leading to a broad array of functions. mentin phosphorylation15. While the effect of S38 Besides emerging research on IF phosphorylation phosphorylation on the vimentin network was not functions and interactions, we are still very much shown, it can be assumed that vimentin assembly in the discovery phase of finding out what each site was disrupted thus enabling proper migration and does and to what physiological processes it contrib- tumorigenesis. utes. In the future, it will be interesting to consid- There is a gradient of vimentin organization er the added diversity brought by cell type-specif- in motile cells, from primarily non-filamentous ic phosphorylation functions. For instance, nestin precursors in the distal regions of lamellipodia, exhibits differential phosphorylation according with vimentin gradually becoming more orga- to cell type, with some nestin phosphosites being nized further away from the lamellipodial edge CNS-specific12. This could be another explanation towards the nucleus, suggesting that vimentin is as to why vimentin C-terminus functions have re- dynamically organized during cell motility16. A mained elusive – they simply have not been inves- cluster of serines at the N-terminus of vimentin, tigated under the right conditions. The majority of including S6, is phosphorylated in a PKCε-de- the validated phosphosites on vimentin are serines. pendent manner which is important for integrin There are also five tyrosine phosphorylation sites on recycling17. During cell spreading, vimentin is the vimentin head-domain that have been identified phosphorylated in a PKCε dependent manner by several independent studies, but none has been at S6, S38, and S50. Filamin A, an actin cross- validated in vivo6. As such all of the discussion on linker, forms a complex with activated PKCε and the phospho-regulation of vimentin is concentrated phosphorylated vimentin, and this is required for on serine phosphorylation. vimentin reorganization in spreading cells18. This has been further verified by studies showing that Vimentin Phosphorylation an organized vimentin network is antagonistic and Cell Migration for lamellipodia formation, but is necessary for Vimentin promotes cell migration which is a establishing cell polarity. Rac induced vimentin co-ordinated process involving the formation of phosphorylation at S38 induces network disas- the leading edge, lamellipodia extension, adhe- sembly and retraction from the lamellipodia pri- 2604 Vimentin and post-translational modifications in cell motility during cancer – a review or to membrane ruffling16. Notably, inhibition of moylation is associated with stress-induced phos- ROCK, a known vimentin kinase, and Rac, an phorylation and ubiquitination, although exactly upstream activator of another vimentin kinase mechanisms remain
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