Receptor-type protein tyrosine phosphatase zeta as a component of the signaling receptor complex for midkine-dependent survival of embryonic neurons

Neurosci Res. 2003 Feb;45(2):219-24. doi: 10.1016/s0168-0102(02)00226-2.


Midkine (MK), a heparin-binding growth factor, suppresses apoptosis of embryonic neurons in culture, induced by serum deprivation. Receptor-type protein tyrosine phosphatase zeta (PTP zeta) is a chondroitin sulfate proteoglycan with a transmembrane domain and intracellular tyrosine phosphatase domains. The activity of MK was abolished by digestion with chondroitinase ABC, or addition of the antibody to PTP zeta, while digestion with heparitinase showed no significant effect. These results suggested that the survival-promoting signal of MK was received by a receptor complex containing PTP zeta. Low density lipoprotein receptor-related protein (LRP) has been identified as another component of the signaling receptor. Ectodomains of two related proteins expressed on neurons, namely LRP6 and apoE receptor 2, were FLAG-tagged and examined for MK binding, using MK-agarose column. Both the ectodomains were found to exhibit calcium-dependent binding to MK. These proteins may participate in MK signaling in certain cases. The survival-promoting activity of MK was abolished by PP1, an inhibitor of src protein kinase, pertussis toxin, an inhibitor of G protein-linked signaling and sodium orthovanadate, an inhibitor of PTPs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Cell Survival
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / enzymology
  • Cytokines*
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mice
  • Mice, Inbred ICR
  • Midkine
  • Neurons / drug effects
  • Neurons / enzymology*
  • Protein Tyrosine Phosphatases / metabolism*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5


  • Carrier Proteins
  • Cytokines
  • Enzyme Inhibitors
  • Midkine
  • PTPRZ1 protein, human
  • Protein Tyrosine Phosphatases
  • Ptprz1 protein, mouse
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5