title: Gα73B is a downstream effector of JAK/STAT signalling and a regulator of Rho1 in Drosophila haematopoiesis.
abstract: JAK/STAT signalling regulates many essential developmental processes including cell proliferation and haematopoiesis, whereas its inappropriate activation is associated with the majority of myeloproliferative neoplasias and numerous cancers. Furthermore, high levels of JAK/STAT pathway signalling have also been associated with enhanced metastatic invasion by cancerous cells. Strikingly, gain-of-function mutations in the single Drosophila JAK homologue, Hopscotch, result in haemocyte neoplasia, inappropriate differentiation and the formation of melanised haemocyte-derived 'tumour' masses; phenotypes that are partly orthologous to human gain-of-function JAK2-associated pathologies. Here we show that Gα73B, a novel JAK/STAT pathway target gene, is necessary for JAK/STAT-mediated tumour formation in flies. In addition, although Gα73B does not affect haemocyte differentiation, it does regulate haemocyte morphology and motility under non-pathological conditions. We show that Gα73B is required for constitutive, but not injury-induced, activation of Rho1 and for the localisation of Rho1 into filopodia upon haemocyte activation. Consistent with these results, we also show that Rho1 interacts genetically with JAK/STAT signalling, and that wild-type levels of Rho1 are necessary for tumour formation. Our findings link JAK/STAT transcriptional outputs, Gα73B activity and Rho1-dependent cytoskeletal rearrangements and cell motility, therefore connecting a pathway associated with cancer with a marker indicative of invasiveness. As such, we suggest a mechanism by which JAK/STAT pathway signalling may promote metastasis.
authors.affiliation: MRC Centre for Development and Biomedical Genetics, and The Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, UK.
authors.forename: Nina
authors.initials: N
authors.lastname: Bausek
authors.forename: Martin P
authors.initials: MP
authors.lastname: Zeidler
mesh_terms: D000818:Animals; D002465:Cell Movement; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis / Q000235:genetics*; D006434:Hemocytes / Q000378:metabolism* / Q000473:pathology; D053612:Janus Kinases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D011554:Pseudopodia / Q000378:metabolism / Q000473:pathology; D050791:STAT Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D044385:GTP-Binding Protein alpha Subunits; C000590844:Galphaf protein, Drosophila; D050791:STAT Transcription Factors; D014157:Transcription Factors; D053612:Janus Kinases; C085845:hop protein, Drosophila; C511153:Rho1 protein, Drosophila; D020741:rho GTP-Binding Proteins
keywords: Drosophila melanogaster; Haematopoiesis; JAK; Rho1; Tumorigenesis