|
Summary of Research Projects (Supports in 2003
Fiscal Year)
| Subjects |
Functional Analysis of Receptor-Type Protein Tyrosine Phosphatase
ζ |
| Representative researcher |
National Institute for Basic Biology Masaharu NODA |
| Protein tyrosine phosphorylation
plays crucial roles in various biological aspects. However,
physiological functions of individual PTPs are poorly understood
due to a lack of information concerning substrates of respective
PTPs. Protein tyrosine phosphatase ζ (PTPζ/RPTPβ/Ptprz)
is a receptor-type PTP predominantly expressed in the brain
as a chondroitin sulfate proteoglycan. We previously revealed
that PTPζ binds pleiotrophin and midkine, closely related
heparin-binding growth factors. We now developed a genetic
method "yeast substrate-trapping system" to isolate substrates
for PTPs, and successfully identified substrate molecules
for PTPζ including Git1 and p190 RhoGAP, together with many
interacting molecules. RPTPs transduce the extracellular
signals through the change of their PTP activity, however,
our knowledge about the regulatory mechanism is still limited.
We demonstrated that oligomers of pleiotrophin dose-dependently
enhance the tyrosine phosphorylation of Git1. PTPζ thus appears
to be constitutively active in the monomeric form and negatively
regulated by dimerization. Furthermore, we found that mutant
mice deficient in PTPζ exhibited enhanced long-term potentiation
(LTP) in the CA1 region of hippocampal slices and impaired
spatial learning abilities in an age-dependent manner. The
enhanced LTP was canceled out by pharmacological inhibition
of Rho-associated kinase (ROCK), a major downstream effector
of Rho. These findings suggest that the lack of PTPζ leads
to aberrant activation of ROCK and resultantly to the enhanced
LTP and learning impairments. |
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