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A role for receptor protein tyrosine phosphatase lambda in midbrain development.

ABSTRACT: The mid-hindbrain boundary (MHB) harbors an important organizing center for the adjacent brain regions. Here, we present evidence that the receptor protein tyrosine phosphatase lambda (RPTPlambda) is part of the complex molecular network that maintains and shapes the MHB region. RPTPlambda is expressed in a tight band of cells in the caudal midbrain, anterior to the transverse ring of Wnt1 expression. Forced expression of RPTPlambda across the mid-hindbrain region repressed expression of Wnt1, whereas RNA interference-mediated knock-down of RPTPlambda resulted in expansion and distortion of the Wnt1 domain. When ectopically expressed in the mesencephalon, RPTPlambda specifically inhibited the induction of Wnt1 expression after subsequent stimulation with Fgf8. Reduced Wnt1 expression after RPTPlambda transfection correlated with a decrease in Ras- mitogen-activated protein kinase activity at the MHB. We further show that in the embryonic midbrain, RPTPlambda can bind to beta-catenin, a central component of the canonical Wnt signaling pathway. Overexpression of RPTPlambda suppressed the activity of a beta-catenin responsive promoter in the midbrain and reduced progenitor cell proliferation. Cotransfection of Wnt1 or of a stabilized form of beta-catenin together with RPTPlambda partially rescued the RPTPlambda-mediated proliferation defect. Together, these data suggest that RPTPlambda may play a dual role in the control of midbrain development: as a negative modulator of Fgf8-induced Wnt1 expression at the MHB, which may help to confine the Wnt1 domain to it characteristic tight ring at the MHB; and as an inhibitor of canonical Wnt signaling through interaction with and presumably sequestration of beta-catenin.

SUBMITTER: Badde A

PROVIDER: S-EPMC6670526 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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A role for receptor protein tyrosine phosphatase lambda in midbrain development.

Badde Anja A Schulte Dorothea D

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080601 24

The mid-hindbrain boundary (MHB) harbors an important organizing center for the adjacent brain regions. Here, we present evidence that the receptor protein tyrosine phosphatase lambda (RPTPlambda) is part of the complex molecular network that maintains and shapes the MHB region. RPTPlambda is expressed in a tight band of cells in the caudal midbrain, anterior to the transverse ring of Wnt1 expression. Forced expression of RPTPlambda across the mid-hindbrain region repressed expression of Wnt1, w ...[more]

PMID: 18550757

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Project description:Fms-like tyrosine kinase 3 (FLT3) plays an important role in hematopoietic differentiation, and constitutively active FLT3 mutant proteins contribute to the development of acute myeloid leukemia. Little is known about the protein-tyrosine phosphatases (PTP) affecting the signaling activity of FLT3. To identify such PTP, myeloid cells expressing wild type FLT3 were infected with a panel of lentiviral pseudotypes carrying shRNA expression cassettes targeting different PTP. Out of 20 PTP tested, expressed in hematopoietic cells, or presumed to be involved in oncogenesis or tumor suppression, DEP-1 (PTPRJ) was identified as a PTP negatively regulating FLT3 phosphorylation and signaling. Stable 32D myeloid cell lines with strongly reduced DEP-1 levels showed site-selective hyperphosphorylation of FLT3. In particular, the sites pTyr-589, pTyr-591, and pTyr-842 involved in the FLT3 ligand (FL)-mediated activation of FLT3 were hyperphosphorylated the most. Similarly, acute depletion of DEP-1 in the human AML cell line THP-1 caused elevated FLT3 phosphorylation. Direct interaction of DEP-1 and FLT3 was demonstrated by "substrate trapping" experiments showing association of DEP-1 D1205A or C1239S mutant proteins with FLT3 by co-immunoprecipitation. Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro. Enhanced FLT3 phosphorylation in DEP-1-depleted cells was accompanied by enhanced FLT3-dependent activation of ERK and cell proliferation. Stable overexpression of DEP-1 in 32D cells and transient overexpression with FLT3 in HEK293 cells resulted in reduction of FL-mediated FLT3 signaling activity. Furthermore, FL-stimulated colony formation of 32D cells expressing FLT3 in methylcellulose was induced in response to shRNA-mediated DEP-1 knockdown. This transforming effect of DEP-1 knockdown was consistent with a moderately increased activation of STAT5 upon FL stimulation but did not translate into myeloproliferative disease formation in the 32D-C3H/HeJ mouse model. The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation.

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A role for receptor protein tyrosine phosphatase lambda in midbrain development.

Publications

A role for receptor protein tyrosine phosphatase lambda in midbrain development.

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