Fragments of SLIT3 inhibit cellular migration

Schubert,Thomas; Denk,Alexandra  E.; Ruedel,Anke; Kaufmann,Simone; Hustert,Elisabeth; Bastone,Patrizia; Bosserhoff,Anja  K.

doi:10.3892/ijmm.2012.1098

Fragments of SLIT3 inhibit cellular migration

Authors:
- Thomas Schubert
- Alexandra E. Denk
- Anke Ruedel
- Simone Kaufmann
- Elisabeth Hustert
- Patrizia Bastone
- Anja K. Bosserhoff
View Affiliations

Affiliations: Institute of Pathology, University of Regensburg, Regensburg, Germany, Scil Technology GmbH, Martinsried, Germany
Published online on: August 20, 2012 https://doi.org/10.3892/ijmm.2012.1098
Pages: 1133-1137

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The repellent factor family of Slit molecules has been described as having a repulsive function in the developing nervous system on growing axons expressing the Roundabout (Robo) receptors. Recent studies determined the effects of Slit molecules on the migratory and invasive potential of several types of tumor cells but also on synovial fibroblasts (SFs) derived from rheumatoid arthritis (RA) patients. To optimize a potential therapeutic application we aimed at generatingfragments of Slit3 showing the same functional ability as the full-length molecule but having the advantage of a smaller size. Recombinant Slit3 proteins were expressed and analyzed by western blotting. Their activity was defined by functional assays such as migration assays with RASF and melanoma cells. Recombinant Slit3 containing only leucine rich repeat domain 2 (D2), the domain important for Robo binding and the minimal functional unit D2 dNC were both able to inhibit migration of RASFs as effectively as Slit3 with all 4 repeats. Collectively, our data showed that the ability of Slit3 to reduce the migratory activity of synovial cells from patients with RA and melanoma cells can be mimicked by small protein fragments derived from Slit3. Slit3 fragments may be helpful in therapeutic attempts; however, further studies are necessary in order to elucidate their activity in vivo.

View Figures

View References

1.	CB GuanHT XuM JinXB YuanMM PooLong-range Ca²⁺ signaling from growth cone to soma mediates reversal of neuronal migration induced by slit-2Cell1293853952007
2.	T YasudaCartilage destruction by matrix degradation productsMod Rheumatol16197205200610.3109/s10165-006-0490-616906368
3.	R AltenE Gromnica-IhleC PohlJ EmmerichJ SteffgenR RoscherR SigmundB SchmolkeG SteinmannInhibition of leukotriene B4-induced CD11B/CD18 (Mac-1) expression by BIIL 284, a new long acting LTB4 receptor antagonist, in patients with rheumatoid arthritisAnn Rheum Dis63170176200410.1136/ard.2002.00449914722206
4.	BJ DicksonGF GilestroRegulation of commissural axon pathfinding by slit and its Robo receptorsAnnu Rev Cell Dev Biol22651675200610.1146/annurev.cellbio.21.090704.15123417029581
5.	JH ChenL WenS DupuisJY WuY RaoThe N-terminal leucine-rich regions in Slit are sufficient to repel olfactory bulb axons and subventricular zone neuronsJ Neurosci2115481556200111222645
6.	S KrasnokutskyJ SamuelsSB AbramsonOsteoarthritis in 2007Bull NYU Hosp Jt Dis652222282007
7.	JY WuL FengHT ParkN HavliogluL WenH TangKB BaconZ JiangX ZhangY RaoThe neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factorsNature410948952200110.1038/3507361611309622
8.	AE DenkS BraigT SchubertAK BosserhoffSlit3 inhibits activator protein 1-mediated migration of malignant melanoma cellsInt J Mol Med28721726201121743955
9.	AE DenkS KaufmannK StarkJ SchedelT LowinT SchubertAK BosserhoffSlit3 inhibits Robo3-induced invasion of synovial fibroblasts in rheumatoid arthritisArthritis Res Ther12R45201010.1186/ar295520298552
10.	S MertschN SchmitzA JeibmannJG GengW PaulusV SennerSlit2 involvement in glioma cell migration is mediated by Robo1 receptorJ Neurooncol8717200810.1007/s11060-007-9484-217968499
11.	MC StellaL TrusolinoPM ComoglioThe Slit/Robo system suppresses hepatocyte growth factor-dependent invasion and morphogenesisMol Biol Cell20642657200910.1091/mbc.E08-03-032119005219
12.	HK KimH ZhangH LiTT WuS SwisherD HeL WuJ XuCA ElmetsM AtharSlit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinomaNeoplasia1014111420200819048120
13.	E HohenesterS HussainJA HowittInteraction of the guidance molecule Slit with cellular receptorsBiochem Soc Trans34418421200610.1042/BST034041816709176
14.	C MorlotNM ThielensRB RavelliW HemrikaRA RomijnP GrosS CusackAA McCarthyStructural insights into the Slit-Robo complexProc Natl Acad Sci USA1041492314928200710.1073/pnas.070531010417848514
15.	U Muller-LadnerC OspeltS GayO DistlerT PapCells of the synovium in rheumatoid arthritisSynovial fibroblasts Arthritis Res Ther9223200710.1186/ar2337
16.	AE DenkM BettstetterPJ WildK HoekF BatailleW DietmaierAK BosserhoffLoss of maspin expression contributes to a more invasive potential in malignant melanomaPigment Cell Res20112119200710.1111/j.1600-0749.2007.00363.x17371437
17.	R StollS LodermeyerAK BosserhoffDetailed analysis of MIA protein by mutagenesisBiol Chem38716011606200610.1515/BC.2006.19917132106
18.	V MajithiaSA GeraciRheumatoid arthritis: diagnosis and managementAm J Med120936939200710.1016/j.amjmed.2007.04.005
19.	R MouawadM SebertJ MichelsJ BlochJP SpanoD KhayatTreatment for metastatic malignant melanoma: old drugs and new strategiesCrit Rev Oncol Hematol742739201010.1016/j.critrevonc.2009.08.00519781957
20.	E AtallahL FlahertyTreatment of metastatic malignant melanomaCurr Treat Options Oncol6185193200510.1007/s11864-005-0002-5
21.	S RajagopalanE NicolasV VivancosJ BergerBJ DicksonCrossing the midline: roles and regulation of Robo receptorsNeuron28767777200010.1016/S0896-6273(00)00152-511163265
22.	KT Nguyen Ba-CharvetK BroseV MarillatT KiddCS GoodmanM Tessier-LavigneC SoteloA ChedotalSlit2-Mediated chemorepulsion and collapse of developing forebrain axonsNeuron22463473199910197527