PubMed Journals: Mol Cell Biol
Source: PMID: 14966296
⇦ ⇨ Mol Cell Biol. 2004 Mar;24(5):2190-201.
Site-selective regulation of platelet-derived
growth factor beta receptor tyrosine phosphorylation
by T-cell protein tyrosine phosphatase.
Persson C(1), Sävenhed C, Bourdeau A, Tremblay
ML, Markova B, Böhmer FD, Haj FG, Neel BG,
Elson A, Heldin CH, Rönnstrand L, Ostman
A, Hellberg C.
(1) Ludwig Institute for Cancer Research,
Uppsala Branch, Biomedical Center, S-751
24 Uppsala, Sweden.
The platelet-derived growth factor (PDGF)
beta receptor mediates mitogenic and chemotactic
signals. Like other tyrosine kinase receptors,
the PDGF beta receptor is negatively regulated
by protein tyrosine phosphatases (PTPs).
To explore whether T-cell PTP (TC-PTP) negatively
regulates the PDGF beta receptor, we compared
PDGF beta receptor tyrosine phosphorylation
in wild-type and TC-PTP knockout (ko) mouse
embryos. PDGF beta receptors were
hyperphosphorylated in TC-PTP ko embryos.
Fivefold-higher ligand-induced receptor
phosphorylation was observed in TC-PTP ko
mouse embryo fibroblasts (MEFs) as well.
Reexpression of TC-PTP partly abolished
this difference. As determined with site-specific
phosphotyrosine antibodies, the extent of
hyperphosphorylation varied among different
autophosphorylation sites. The phospholipase
Cgamma1 binding site Y1021, previously implicated
in chemotaxis, displayed the largest increase
in phosphorylation. The increase in Y1021
phosphorylation was accompanied by increased
phospholipase Cgamma1 activity and migratory
hyperresponsiveness to PDGF. PDGF beta receptor
tyrosine phosphorylation in PTP-1B ko MEFs
but not in PTPepsilon ko MEFs was also higher
than that in control cells. This increase
occurred with a site distribution different
from that seen after TC-PTP depletion. PDGF-induced
migration was not increased in PTP-1B ko
cells. In summary, our findings identify
TC-PTP as a previously unrecognized negative
regulator of PDGF beta receptor signaling
and support the general notion that PTPs
display site selectivity in their action
on tyrosine kinase receptors.
PMCID: PMC350555 PMID: 14966296 [Indexed