A conserved interaction between beta1 integrin/PAT-3 and Nck-interacting kinase/MIG-15 that mediates commissural axon navigation in C. elegans

Curr Biol. 2002 Apr 16;12(8):622-31. doi: 10.1016/s0960-9822(02)00764-9.

Abstract

Background: Integrins are heterodimeric (alphabeta) transmembrane receptors for extracellular matrix (ECM) ligands. Through interactions with molecular partners at cell junctions, they provide a connection between the ECM and the cytoskeleton and regulate many aspects of cell behavior. A number of integrin-associated molecules have been identified; however, in many cases, their function and role in the animal remain to be clarified.

Results: We have identified the Nck-interacting kinase (NIK), a member of the STE20/germinal center kinase (GCK) family, as a partner for the beta1A integrin cytoplasmic domain. We find that NIK is expressed in the nervous system and other tissues in mouse embryos and colocalizes with actin and beta1 integrin in cellular protrusions in transfected cells. To demonstrate the functional significance of this interaction, we used Caenorhabditis elegans, since it has only one beta (PAT-3) integrin chain, two alpha (INA-1 and PAT-2) integrin chains, and a well-conserved NIK ortholog (MIG-15). Using three methods, we show that reducing mig-15 activity results in premature branching of commissures. A significant aggravation of this defect is observed when mig-15 activity is compromised in a weak ina-1 background. Neuronal-specific RNA interference against mig-15 or pat-3 leads to similar axonal defects, thus showing that both mig-15 and pat-3 act cell autonomously in neurons. Finally, we show a genetic interaction between mig-15, ina-1, and genes that encode Rac GTPases.

Conclusions: Using several models, we provide the first evidence that the kinase NIK and integrins interact in vitro and in vivo. This interaction is required for proper axonal navigation in C. elegans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Amino Acid Sequence
  • Animals
  • Axons / metabolism*
  • Binding Sites
  • COS Cells
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Line
  • Cell Movement
  • HeLa Cells
  • Humans
  • Integrin beta1 / chemistry
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism*
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Molecular Sequence Data
  • Nervous System / embryology
  • Nervous System / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sequence Homology, Amino Acid
  • Two-Hybrid System Techniques
  • rac GTP-Binding Proteins / metabolism

Substances

  • Actins
  • Caenorhabditis elegans Proteins
  • Integrin beta1
  • Intracellular Signaling Peptides and Proteins
  • MAP4K4 protein, human
  • Protein-Serine-Threonine Kinases
  • rac GTP-Binding Proteins