The Roles of the Protein Tyrosine Phosphatases PTPN3 and PTPN4 in T cells and PTPN11 in Tissue Remodeling.
dc.contributor.author | Bauler, Timothy J. | en_US |
dc.date.accessioned | 2009-09-03T14:50:17Z | |
dc.date.available | 2009-09-03T14:50:17Z | |
dc.date.issued | 2009 | en_US |
dc.date.submitted | 2009 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/63776 | |
dc.description.abstract | PTPN3 and PTPN4 are closely-related non-receptor protein tyrosine phosphatases (PTP) that contain FERM and PDZ domains. Both PTP have been implicated as negative-regulators of early signal transduction through the TCR, acting to dephosphorylate the TCRzeta chain. To determine if PTPN3 functions as a physiological negative-regulator of TCR signaling in primary T cells we generated gene-trapped and gene-targeted mouse strains that lack expression of catalytically-active PTPN3. Numbers and ratios of T cells in primary and secondary lymphoid organs and TCR-induced signal transduction, cytokine production, and proliferation were normal in PTPN3-deficient mice. To address if the lack of a T cell phenotype in PTPN3-deficient mice can be explained by functional redundancy of PTPN3 with PTPN4, we generated PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. As in PTPN3 mutants, T cell development and homeostasis and TCR-induced cytokine synthesis and proliferation were found to be normal in PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. PTPN13 is another FERM and PDZ domain-containing PTP that is distantly related to PTPN3 and PTPN4. Therefore, to determine if PTPN13 might compensate for the loss of PTPN3 and PTPN4 in T cells, we generated mice that lack functional forms of all three PTP. However, triple-mutant T cells are phenotypically indistinguishable from PTPN13 single-deficient T cells. We conclude that PTPN3 and PTPN4 are dispensable for TCR signal transduction. SHP-2 (PTPN11) is essential for signaling from multiple classes of cell surface receptors. Mice deficient in SHP-2 expression exhibit defective gastrulation and fail to survive, which has precluded the use of non-conditional SHP-2 deficient mice to examine the role of SHP-2 in mature animals. To study this, we have used a conditional SHP-2 deficient mutant together with an ubiquitin promoter-driven ERT2-Cre transgene to mediate drug inducible deletion of SHP-2 in multiple tissues in adult mice. Using this model, we have determined that induced deletion of SHP-2 results in lethality preceded by weight loss. Epidermal acanthosis, anemia and premature thymic involution were also observed in these mice. Roles for SHP-2 in the homeostasis of the skeletal system are further demonstrated by the striking bone and cartilage remodeling defects resulting from the loss of SHP-2 in this model. | en_US |
dc.format.extent | 3138931 bytes | |
dc.format.extent | 1373 bytes | |
dc.format.mimetype | application/pdf | |
dc.format.mimetype | text/plain | |
dc.language.iso | en_US | en_US |
dc.subject | Immunology | en_US |
dc.subject | Signal Transduction | en_US |
dc.subject | Protein Tyrosine Phosphatase | en_US |
dc.title | The Roles of the Protein Tyrosine Phosphatases PTPN3 and PTPN4 in T cells and PTPN11 in Tissue Remodeling. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Microbiology & Immunology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | King, Philip D. | en_US |
dc.contributor.committeemember | Dunnick, Wesley | en_US |
dc.contributor.committeemember | Maillard, Ivan Patrick | en_US |
dc.contributor.committeemember | O'Riordan, Mary X D | en_US |
dc.subject.hlbsecondlevel | Microbiology and Immunology | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/63776/1/tjbauler_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.