alpha4beta1- and alpha6beta1-integrins are functional receptors for midkine, a heparin-binding growth factor

J Cell Sci. 2004 Oct 15;117(Pt 22):5405-15. doi: 10.1242/jcs.01423. Epub 2004 Oct 5.


Midkine is a heparin-binding growth factor that promotes the growth, survival, migration and differentiation of various target cells. So far, receptor-type protein tyrosine phosphatase zeta, low-density-lipoprotein-receptor-related protein and anaplastic lymphoma kinase have been identified as receptors for midkine. We found beta1 integrin in midkine-binding proteins from 13-day-old mouse embryos. beta1-Integrin bound to a midkine-agarose column and was eluted mostly with EDTA. Further study revealed that the alpha-subunits capable of binding to midkine were alpha4 and alpha6. Purified alpha4beta1- and alpha6beta1-integrins bound midkine. Anti-alpha4 antibody inhibited the midkine-dependent migration of osteoblastic cells, and anti-alpha6 antibody inhibited the midkine-dependent neurite outgrowth of embryonic neurons. After midkine treatment, tyrosine phosphorylation of paxillin, an integrin-associated molecule, was transiently increased in osteoblastic cells. Therefore, we concluded that alpha4beta1- and alpha6beta1-integrins are functional receptors for midkine. We observed that the low-density-lipoprotein-receptor-related-protein-6 ectodomain was immunoprecipitated with alpha6beta1-integrin and alpha4beta1-integrin. The low-density-lipoprotein-receptor-related-protein-6 ectodomain was also immunoprecipitated with receptor-type protein tyrosine phosphatase zeta. alpha4beta1- and alpha6beta1-Integrins are expected to co-operate with other midkine receptors, possibly in a multimolecular complex that contains other midkine receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Blotting, Western
  • COS Cells
  • Cell Line, Tumor
  • Cell Movement
  • Cytokines / metabolism*
  • Cytoskeletal Proteins / metabolism
  • Drosophila melanogaster
  • Embryo, Nonmammalian / metabolism
  • Gene Deletion
  • Growth Substances / metabolism*
  • Heparin / metabolism*
  • Immunoprecipitation
  • Integrin alpha4beta1 / physiology*
  • Integrin alpha6beta1 / physiology*
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
  • Mice
  • Midkine
  • Mutation
  • Neurons / metabolism
  • Paxillin
  • Phosphoproteins / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Tyrosine Phosphatases / metabolism
  • Rats
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5
  • Time Factors
  • Tyrosine / metabolism


  • Cytokines
  • Cytoskeletal Proteins
  • Growth Substances
  • Integrin alpha4beta1
  • Integrin alpha6beta1
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Paxillin
  • Phosphoproteins
  • Pxn protein, mouse
  • Pxn protein, rat
  • Midkine
  • Tyrosine
  • Heparin
  • Protein Tyrosine Phosphatases
  • Ptprz1 protein, mouse
  • Ptprz1 protein, rat
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5