title: Mechanism of cell-intrinsic adaptation to Adams-Oliver Syndrome gene DOCK6 disruption highlights ubiquitin-like modifier ISG15 as a regulator of RHO GTPases.
abstract: DOCK6 is a RAC1/CDC42 guanine nucleotide exchange factor, however, little is known about its function and sub-cellular localization. DOCK6 regulates the balance between RAC1 and RHOA activity during cell adhesion and is important for CDC42-dependent mitotic chromosome alignment. Surprisingly, a cell intrinsic adaptation mechanism compensates for errors in these DOCK6 functions that arise as a consequence of prolonged DOCK6 depletion or complete removal in DOCK6 knockout cells. Down-regulation of the ubiquitin-like modifier ISG15 accounts for this adaptation. Strikingly, although most other DOCK family proteins are deployed on the plasma membrane, here we show that DOCK6 localizes to the endoplasmic reticulum (ER) in dependence of its DHR-1 domain. ER localization of DOCK6 opens up new insights into its functions.
authors.affiliation: a Zentrum für Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Allianz , Heidelberg , Germany.
authors.forename: Berati
authors.initials: B
authors.lastname: Cerikan
authors.affiliation: a Zentrum für Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Allianz , Heidelberg , Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Schiebel
mesh_terms: D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012536:Scalp Dermatoses / Q000151:congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; C000607938:DOCK6 protein, human; D020662:Guanine Nucleotide Exchange Factors; C107953:RAC1 protein, human; D014452:Ubiquitins; C066737:RHOA protein, human; C074034:ISG15 protein, human; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
keywords: Adams-Oliver Syndrome; CRISPR/Cas9; DOCK6; ISG15