This proposal describes experiments that will seek to understand adhesion molecule function during nervous system development, and how specific connections are formed through the regulated action of cell adhesion molecules. The goal of the application is to understand how adhesion molecules regulate intracellular signaling events. The applicant will focus work on a recently described and poorly understood class of adhesion molecules, the receptor protein tyrosine phosphatases (RPTPs). The applicant has focused on PTPu, a unique RPTP that contains structural components similar to immunoglobulin superfamily proteins, cadherin adhesion molecules and PTPs. Previous studies by the applicant showed that the extracellular segment of PTPu mediates cell aggregation through homophilic binding of the immunoglobulin domain. Also, the intracellular domain of PTPu has catalytic activity and associates with cadherins. PTPu may signal in response to cell adhesion. This proposal will address the mechanism by which PTPu sends adhesive signals and the biological significance of this signal transduction. PTPu is abundant in many parts of the adult central nervous system and is developmentally regulated in the retina. The retina is one of the best characterized and experimentally tractable systems for studying both cell adhesion and development, particularly for neuronal migration and retinal layer formation (lamination) during development. Preliminary studies demonstrated that PTPu promotes neurite outgrowth of chick retinal ganglion cells.
Three specific aims are proposed: (1) to determine whether PTPu phosphatase activity is required to induce neurite outgrowth on PTPu or N-cadherin substrates by: (a) determining the role of the PTPu phosphatase in the promotion of neurite outgrowth of chick retinal ganglion cell neurons, and (b) assessing the involvement of PTPu in regulation of the cytoskeleton using chick retinal ganglion cell neurons in border crossing assays; (2) to determine what signaling pathways are used by PTPu to transduce signals in response to adhesion by: (a) identifying downstream targets or substrates of PTPu; and (b) analyzing PTPu signal transduction pathway(s) in primary chick retinal cell cultures; and (3) to determine whether PTPu regulates retinal development by (a) investigating the role of PTPu in lamination of the chick retina during development; and (b) analyzing the role of PTPu in pathfinding of chick retinal ganglion cells during projection to the optic tectum.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY012251-01
Application #
2677991
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1998-09-30
Project End
2001-09-29
Budget Start
1998-09-30
Budget End
1999-09-29
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Oblander, Samantha A; Brady-Kalnay, Susann M (2010) Distinct PTPmu-associated signaling molecules differentially regulate neurite outgrowth on E-, N-, and R-cadherin. Mol Cell Neurosci 44:78-93
Phillips-Mason, Polly J; Mourton, Tracy; Major, Denice L et al. (2008) BCCIP associates with the receptor protein tyrosine phosphatase PTPmu. J Cell Biochem 105:1059-72
Yu, Jianshi; Becka, Scott; Zhang, Peng et al. (2008) Tumor-derived extracellular mutations of PTPRT /PTPrho are defective in cell adhesion. Mol Cancer Res 6:1106-13
Oblander, Samantha A; Ensslen-Craig, Sonya E; Longo, Frank M et al. (2007) E-cadherin promotes retinal ganglion cell neurite outgrowth in a protein tyrosine phosphatase-mu-dependent manner. Mol Cell Neurosci 34:481-92
Major, Denice L; Brady-Kalnay, Susann M (2007) Rho GTPases regulate PTPmu-mediated nasal neurite outgrowth and temporal repulsion of retinal ganglion cell neurons. Mol Cell Neurosci 34:453-67
Xie, Youmei; Massa, Stephen M; Ensslen-Craig, Sonya E et al. (2006) Protein-tyrosine phosphatase (PTP) wedge domain peptides: a novel approach for inhibition of PTP function and augmentation of protein-tyrosine kinase function. J Biol Chem 281:16482-92
Phillips-Mason, Polly J; Gates, Theresa J; Major, Denice L et al. (2006) The receptor protein-tyrosine phosphatase PTPmu interacts with IQGAP1. J Biol Chem 281:4903-10
Ensslen-Craig, Sonya E; Brady-Kalnay, Susann M (2005) PTP mu expression and catalytic activity are required for PTP mu-mediated neurite outgrowth and repulsion. Mol Cell Neurosci 28:177-88
Ensslen-Craig, Sonya E; Brady-Kalnay, Susann M (2004) Receptor protein tyrosine phosphatases regulate neural development and axon guidance. Dev Biol 275:12-22
Ensslen, Sonya E; Brady-Kalnay, Susann M (2004) PTPmu signaling via PKCdelta is instructive for retinal ganglion cell guidance. Mol Cell Neurosci 25:558-71

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