The cellular story of dishevelleds

Kafka, Anja and Bašić-Kinda, Sandra and Pećina-Šlaus, Nives (2014) The cellular story of dishevelleds. Croatian Medical Journal, 55 (5). pp. 459-467. ISSN 0353-9504

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Abstract

Dishevelled (DVL) proteins, three of which have been identified in humans, are highly conserved components of canonical and noncanonical Wnt signaling pathways. These multifunctional proteins, originally discovered in the fruit fly, through their different domains mediate complex signal transduction: DIX (dishevelled, axin) and PDZ (postsynaptic density 95, discs large, zonula occludens-1) domains serve for canonical beta-catenin signaling, while PDZ and DEP (dishevelled, Egl-10, pleckstrin) domains serve for non-canonical signaling. In canonical or beta-catenin signaling, DVL forms large molecular supercomplexes at the plasma membrane consisting of Wnt-Fz-LRP5/6-DVL-AXIN. This promotes the disassembly of the beta-catenin destruction machinery, beta-catenin accumulation, and consequent activation of Wnt signaling. Therefore, DVLs are considered to be key regulators that rescue cytoplasmic beta-catenin from degradation. The potential medical importance of DVLs is in both human degenerative disease and cancer. The overexpression of DVL has been shown to potentiate the activation of Wnt signaling and it is now apparent that up-regulation of DVLs is involved in several types of cancer.

Abstract in Croatian

Stanična priča proteina dishevelled ----- Proteini dishevelled (DVL), od kojih su tri identificirana kod ljudi, visoko su očuvane molekularne sastavnice kanoničkog i nekanoničkog signalnog puta Wnt. Ovi multifunkcionalni proteini, koji su prvi put otkriveni kod vinske mušice, preko svojih različitih domena posreduju složeni prijenos signala: domene DIX (dishevelled, aksin) i PDZ (postsinaptička gustoća 95, discs large, zonula okludens-1) služe za kanoničko beta-katenin signaliziranje, dok PDZ i DEP (dishevelled, Egl-10, plekstrin) služe za nekanoničko signaliziranje. Kod kanoničkog ili signaliziranja putem beta-katenina, DVL na citoplazmatskoj membrani stvara velike molekularne komplekse, koji se sastoje od Wnt-Fz-LRP5/6-DVL-AXIN. Ovo dovodi do razlaganja stanične mašinerije za uništavanje beta-katenina, njegovog nakupljanja te konačno do aktivacije signalnog puta Wnt. Stoga, dishevellede smatramo ključnim regulatorima koji spašavaju citoplazmatski beta-katenin od razgradnje. Proteini DVL mogu imati potencijalnu važnost u liječenju degenerativnih bolesti i tumora. Poznato je da prekomjerna ekspresija DVL-a potencira aktivaciju signala Wnt te da do prekomjerne ekspresije DVL-a dolazi kod nekoliko vrsta karcinoma.

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