The Drosophila Midkine/Pleiotrophin Homologues Miple1 and Miple2 Affect Adult Lifespan but Are Dispensable for Alk Signaling during Embryonic Gut Formation

Abstract

Midkine (MDK) and Pleiotrophin (PTN) are small heparin-binding cytokines with closely related structures. The Drosophila genome harbours two genes encoding members of the MDK/PTN family of proteins, known as miple1 and miple2. We have investigated the role of Miple proteins in vivo, in particular with regard to their proposed role as ligands for the Alk receptor tyrosine kinase (RTK). Here we show that Miple proteins are neither required to drive Alk signaling during Drosophila embryogenesis, nor are they essential for development in the fruit fly. Additionally we show that neither MDK nor PTN can activate hALK in vivo when ectopically co-expressed in the fly. In conclusion, our data suggest that Alk is not activated by MDK/PTN related growth factors Miple1 and Miple 2 in vivo.

FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase

“…The identity of a ligand(s) for vertebrate ALK has been an evolving question for many years, with a number of reports over the past 15 years examining the role of the small heparin binding growth factors MDK and PTN as ligands for vertebrate ALK ( Stoica et al, 2001 ; Stoica et al, 2002 ). However, a number of independent studies including our own work have presented convincing evidence that MDK and PTN do not activate ALK ( Motegi et al, 2004 ; Moog-Lutz et al, 2005 ; Mourali et al, 2006 ; Mathivet et al, 2007 ; Hugosson et al, 2014 ; Murray et al, 2015 ). The recent identification of long chain heparins as activators of ALK in neuroblastoma cells ( Murray et al, 2015 ) and the interplay of this with ALK activation by FAM150A and FAM150B will require further work.…”

“…Expression of either FAM150A or FAM150B in the developing eye, using the GMR-Gal4 driver, resulted in normal eye morphology ( Figure 3A ). In contrast, expression of constitutively active ALK-F1174S described in neuroblastoma patients results in a rough eye morphology ( Figure 3A ) ( Martinsson et al, 2011 ), while no eye phenotype was observed upon the expression of wild-type human ALK alone ( Figure 3A ) ( Martinsson et al, 2011 , Schonherr, Ruuth et al, 2011 , Schonherr, Ruuth et al, 2011 , Chand et al, 2013 ; Hugosson et al, 2014 ). This can be compared with coexpression of either FAM150A or FAM150B together with human ALK which led to a rough eye phenotype, proving that both FAM150A and FAM150B were able to activate human ALK in this in vivo system ( Figure 3A, B ).…”

“…We next analyzed the ability of FAM150A or FAM150B to activate human ALK in a Drosophila model, which offers a clear readout. Neither the Drosophila Alk ligand Jeb ( Englund et al, 2003 ; Lee et al, 2003 ; Stute et al, 2004 ) nor previously proposed vertebrate ligands, that is, human midkine (MDK) and pleiotrophin (PTN) are able to activate either mouse or human ALK ( Yang et al, 2007 ; Hugosson et al, 2014 ). Expression of either FAM150A or FAM150B in the developing eye, using the GMR-Gal4 driver, resulted in normal eye morphology ( Figure 3A ).…”

Identification of the Wallenda JNKKK as an Alk suppressor reveals increased competitiveness of Alk-expressing cells

“…We previously showed that the signaling activity of Drosophila and human ALK receptors can be assessed in the fly eye 4,[26][27][28][29][30][31]36 . When Drosophila Alk was ectopically expressed in the developing eye under control of the sevEP-Gal4 driver, we observed severe loss of ommatidia and patches of necrotic tissue in the anterior part of the adult fly eye as well as a "rough-eye-morphology" in the posterior part ( Fig.…”

Leukocyte receptor tyrosine kinase interacts with secreted midkine to promote survival of migrating neural crest cells

“…The ligand for the LTK/ALK ortholog in Drosophila is the LDLa domaincontaining ligand jelly belly ( jeb), but an obvious ortholog is absent from vertebrate genomes (Lee et al, 2003;Weiss et al, 2001). After the first reports implicating midkine/pleiotrophin as ligands for ALK (Stoica et al, 2001(Stoica et al, , 2002, different groups failed to replicate activation of ALK by either putative ligand, placing the existence of these interactions in question (Dirks et al, 2002;Hugosson et al, 2014;Mathivet et al, 2007;Miyake et al, 2002;Moog-Lutz et al, 2005;Motegi et al, 2004;Mourali et al, 2006;Müller-Tidow et al, 2005). In contrast, our data are consistent with a ligand-receptor interaction.…”