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You searched for +publisher:"University of Michigan" +contributor:("Shimizu, Yoji"). Showing records 1 – 3 of 3 total matches.

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University of Michigan

1. Chan, Sin-Hang. Regulation of beta1 integrin functional activity by the CD7 antigen in human T lymphocytes.

Degree: PhD, Molecular biology, 1998, University of Michigan

Modulation of the functional activity of integrin adhesion receptors on T lymphocytes is a dynamic process initiated by activation of cell surface receptors. On human T cells, antibody-mediated crosslinking of the CD7 antigen results in a rapid increase in the functional activity of β1 and β2 integrin receptors. The objective of this thesis is to elucidate the intracellular signaling pathway utilized by CD7 to regulate β1 integrin function on human T lymphocytes. The kinetics of CD7-mediated activation of integrin function was distinct from that observed following phorbol ester stimulation and anti-CD3 crosslinking. CD7 stimulation also did not induce an increase in CD2-mediated adhesion to LFA-3. A role for tyrosine kinases in CD7 regulation of integrin function is suggested, since CD7 stimulation results in increased tyrosine phosphorylation and CD7-mediated activation of integrin function is blocked by tyrosine kinase inhibitors. Stimulation of CD7 was also found to induce the association of CD7 with the p85 subunit of phosphatidylinositol 3-kinase (PI 3-K) via tyrosine phosphorylation of the CD7 cytoplasmic SH2 binding motif, tyr-glu-asp-met (YEDM). Treatment of T cells with two structurally distinct PI 3-K inhibitors blocked CD7-mediated activation of integrin function. In addition, expression of a dominant-negative form of the p85 subunit of PI 3-K specifically inhibited CD7-mediated increases in integrin-mediated T cell adhesion. The role of the CD7 cytoplasmic domain in activating PI 3-K and integrin function was investigated further by expressing chimeric receptors containing the CD7 cytoplasmic domain in the myelomonocytic cell line HL60. Stimulation of chimeric receptors containing the wild-type CD7 cytoplasmic domain resulted in tyrosine phosphorylation, as well as association and activation of PI 3-K. Stimulation of chimeric receptors containing the CD7 cytoplasmic domain with a deletion of the YEDM motif resulted in a similar pattern of tyrosine phosphorylation but failed to associate with and activate PI 3-K. However, neither chimeric receptor was able to increase βI integrin-mediated adhesion of HL60 cells to fibronectin. In summary, these results suggest that PI 3-K is necessary but not sufficient for CD7-mediated regulation of integrin-mediated adhesion. Advisors/Committee Members: Shimizu, Yoji (advisor), Imperiale, Michael J. (advisor).

Subjects/Keywords: Activity; Beta1; Cd7 Antigen; Functional; Human; Integrin; Regulation; T Lymphocytes

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APA (6th Edition):

Chan, S. (1998). Regulation of beta1 integrin functional activity by the CD7 antigen in human T lymphocytes. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/131365

Chicago Manual of Style (16th Edition):

Chan, Sin-Hang. “Regulation of beta1 integrin functional activity by the CD7 antigen in human T lymphocytes.” 1998. Doctoral Dissertation, University of Michigan. Accessed April 10, 2021. http://hdl.handle.net/2027.42/131365.

MLA Handbook (7th Edition):

Chan, Sin-Hang. “Regulation of beta1 integrin functional activity by the CD7 antigen in human T lymphocytes.” 1998. Web. 10 Apr 2021.

Vancouver:

Chan S. Regulation of beta1 integrin functional activity by the CD7 antigen in human T lymphocytes. [Internet] [Doctoral dissertation]. University of Michigan; 1998. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/2027.42/131365.

Council of Science Editors:

Chan S. Regulation of beta1 integrin functional activity by the CD7 antigen in human T lymphocytes. [Doctoral Dissertation]. University of Michigan; 1998. Available from: http://hdl.handle.net/2027.42/131365


University of Michigan

2. Zell, Traci. Two mechanisms of beta1 integrin regulation in human leukocytes.

Degree: PhD, Molecular biology, 1997, University of Michigan

Cell adhesion plays a fundamental role in controlling normal cellular behavior. Integrins are a large family of adhesion molecules that play an important role in mediating lymphocyte interactions with other cells and with components of the extracellular matrix. The distinct array of integrins expressed on the surface of a cell at any given time dictate the spectrum of ECM and cell surface ligands with which the cell can interact. Changes in integrin expression can dramatically affect lymphocyte recirculation and activation. Unlike most cell types in the body that continuously stay in a distinct anatomical location, cells of the immune system require the ability to alternate between adhesive and nonadhesive states in order to function properly. Normal lymphocyte recirculation requires that cells be in a relatively nonadherent state so that rapid movement throughout the vascular and lymphatic systems is not impeded. Movement of cells into peripheral lymphoid organs and other tissues, where antigen recognition occurs, involves a multi-step adhesion process that allows circulating cells to slow down and extravasate through the vascular endothelium. This thesis addresses two important mechanisms that influence lymphocyte adhesion: (1) regulation of cell surface β1 integrin expression and (2) activation-dependent regulation of β1 integrin function. Results using normal Jurkat T cells and α4-deficient Jurkat cells have suggested potential mechanisms that might be used by lymphocytes to regulate cell surface expression of β1 integrins. These studies indicate that expression of individual α subunits may be regulated differently in lymphocytes. Our results suggest a role for both post-transcriptional and post-translation control of α2 subunit protein expression and a role for post-transcriptional regulation of the α5 subunit. In addition, re-expression experiments suggest that the presence of α4 protein may influence cell surface expression of other a subunits. Studies with HL60 transfectants expressing CD2/28 chimeric receptors have implicated phosphatidylinositol 3-kinase (PI 3-K) as playing an important role in the ability of CD28 to regulate integrin-mediated adhesion. However, substitution of the CD28 SH2-binding motif YMNM with the YVKM motif from CTLA-4 indicated that recruitment and activation of PI 3-K is not a sufficient signal to upregulate β1 integrin-mediated adhesion since this receptor could still mediate PI 3-K activation but not integrin upregulation. Advisors/Committee Members: Shimizu, Yoji (advisor), Koomey, J. Michael (advisor).

Subjects/Keywords: Adhesion; Beta1; Human; Integrin; Leukocytes; Mechanisms; Pi 3-k; Regulation; Two

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APA (6th Edition):

Zell, T. (1997). Two mechanisms of beta1 integrin regulation in human leukocytes. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/130404

Chicago Manual of Style (16th Edition):

Zell, Traci. “Two mechanisms of beta1 integrin regulation in human leukocytes.” 1997. Doctoral Dissertation, University of Michigan. Accessed April 10, 2021. http://hdl.handle.net/2027.42/130404.

MLA Handbook (7th Edition):

Zell, Traci. “Two mechanisms of beta1 integrin regulation in human leukocytes.” 1997. Web. 10 Apr 2021.

Vancouver:

Zell T. Two mechanisms of beta1 integrin regulation in human leukocytes. [Internet] [Doctoral dissertation]. University of Michigan; 1997. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/2027.42/130404.

Council of Science Editors:

Zell T. Two mechanisms of beta1 integrin regulation in human leukocytes. [Doctoral Dissertation]. University of Michigan; 1997. Available from: http://hdl.handle.net/2027.42/130404


University of Michigan

3. Finkelstein, Lisa Deborah. Alpha4-beta1 integrin-mediated signal transduction in human leukocytes.

Degree: PhD, Mechanical engineering, 1998, University of Michigan

Cell adhesion plays a vital role in many cellular processes. Integrin receptors are a family of adhesion molecules that are composed of noncovalently linked α and β subunits. β1 integrins expressed on the cell surface are involved in mediating interactions with the extracellular matrix and with other cells. Most cells in the body use β1 integrins to maintain tight adhesion and remain in a fixed location. However, cells of the immune system, which circulate through the body, must precisely regulate β1 integrin receptors from less adhesive to more adhesive states depending on the needs of the cell. In addition to acting as adhesion molecules, β1 integrins can transduce signals from the external environment to the interior of the cell. These signals may be critical for the cell to function properly. This thesis examines two aspects of β1 integrin-mediated signal transduction pathways in leukocytes. First, the structural requirements for β1-mediated tyrosine phosphorylation in a human T cell line were elucidated. A chimeric CD2/β1 receptor, composed of the β1 cytoplasmic domain and the extracellular and transmembrane portions of CD2, was employed to demonstrate that the β1 cytoplasmic domain is sufficient for increased tyrosine phosphorylation of three substrates, HEF1, pp105, and pp115. Analysis of β1 cytoplasmic domain truncations demonstrated that the five carboxy-terminal amino acids, KYEGK, were critical for the increased tyrosine phosphorylation of all three substrates. Second, the α4β1 signaling cascade in a human monocytic cell line was explored. In the HL60 myelomonocytic cell line, α4β1 engagement resulted in increased tyrosine phosphorylation of the Cbl adaptor protein and association of Cbl with the p85 subunit of phosphatidylinositol 3-kinase (PI 3-K). Subsequently, PI 3-K was activated, and α4β1 stimulation also resulted in increased mitogen activated protein kinase (MAPK) activity. Inhibitor studies and expression of a dominant negative PI 3-K demonstrated that PI 3-K was required for α4β1-stimulated MAPK activity. Furthermore, overexpression analyses revealed that the Cbl adaptor protein was a key component in the α4β1 signaling pathway. Collectively, the results presented in this thesis expand our understanding of β1 integrin-mediated signal transduction. Advisors/Committee Members: Shimizu, Yoji (advisor), Imperiale, Michael (advisor).

Subjects/Keywords: Alpha(4)beta(1) Integrin; Alpha4; Beta1; Human; Leukocytes; Mediated; Signal; Transduction

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Finkelstein, L. D. (1998). Alpha4-beta1 integrin-mediated signal transduction in human leukocytes. (Doctoral Dissertation). University of Michigan. Retrieved from http://hdl.handle.net/2027.42/130953

Chicago Manual of Style (16th Edition):

Finkelstein, Lisa Deborah. “Alpha4-beta1 integrin-mediated signal transduction in human leukocytes.” 1998. Doctoral Dissertation, University of Michigan. Accessed April 10, 2021. http://hdl.handle.net/2027.42/130953.

MLA Handbook (7th Edition):

Finkelstein, Lisa Deborah. “Alpha4-beta1 integrin-mediated signal transduction in human leukocytes.” 1998. Web. 10 Apr 2021.

Vancouver:

Finkelstein LD. Alpha4-beta1 integrin-mediated signal transduction in human leukocytes. [Internet] [Doctoral dissertation]. University of Michigan; 1998. [cited 2021 Apr 10]. Available from: http://hdl.handle.net/2027.42/130953.

Council of Science Editors:

Finkelstein LD. Alpha4-beta1 integrin-mediated signal transduction in human leukocytes. [Doctoral Dissertation]. University of Michigan; 1998. Available from: http://hdl.handle.net/2027.42/130953

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