title: The MADD-3 LAMMER Kinase Interacts with a p38 MAP Kinase Pathway to Regulate the Display of the EVA-1 Guidance Receptor in Caenorhabditis elegans.
abstract: The proper display of transmembrane receptors on the leading edge of migrating cells and cell extensions is essential for their response to guidance cues. We previously discovered that MADD-4, which is an ADAMTSL secreted by motor neurons in Caenorhabditis elegans, interacts with an UNC-40/EVA-1 co-receptor complex on muscles to attract plasma membrane extensions called muscle arms. In nematodes, the muscle arm termini harbor the post-synaptic elements of the neuromuscular junction. Through a forward genetic screen for mutants with disrupted muscle arm extension, we discovered that a LAMMER kinase, which we call MADD-3, is required for the proper display of the EVA-1 receptor on the muscle's plasma membrane. Without MADD-3, EVA-1 levels decrease concomitantly with a reduction of the late-endosomal marker RAB-7. Through a genetic suppressor screen, we found that the levels of EVA-1 and RAB-7 can be restored in madd-3 mutants by eliminating the function of a p38 MAP kinase pathway. We also found that EVA-1 and RAB-7 will accumulate in madd-3 mutants upon disrupting CUP-5, which is a mucolipin ortholog required for proper lysosome function. Together, our data suggests that the MADD-3 LAMMER kinase antagonizes the p38-mediated endosomal trafficking of EVA-1 to the lysosome. In this way, MADD-3 ensures that sufficient levels of EVA-1 are present to guide muscle arm extension towards the source of the MADD-4 guidance cue.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.|The Collaborative Programme in Developmental Biology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Serena A
authors.initials: SA
authors.lastname: D'Souza
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Luckshi
authors.initials: L
authors.lastname: Rajendran
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bagg
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Louis
authors.identifier: 0000-0001-5251-0932
authors.initials: L
authors.lastname: Barbier
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Derek M
authors.initials: DM
authors.lastname: van Pel
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Houtan
authors.initials: H
authors.lastname: Moshiri
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.|The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.|The Collaborative Programme in Developmental Biology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Roy
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000075385:Netrins; D009469:Neuromuscular Junction / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C426649:CUP-5 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C523438:EVA-1 protein, C elegans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000075385:Netrins; C551653:TRIM-9 protein, C elegans; C102174:UNC-40 protein, C elegans; C078146:UNC-6 protein, C elegans; C000609795:MADD-3 kinase, C elegans; D048051:p38 Mitogen-Activated Protein Kinases; C000593038:RAB-7 protein, C elegans; D020691:rab GTP-Binding Proteins