Thesis--Catholic University of America. / "Selected bibliography": p. 129-132.

Thesis (Ph. D.)--University of Western Sydney, Nepean, 2000. / Includes bibliographical references (leaves 203-235).

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1982. / Extra t.p. with thesis statement inserted. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M. A.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Würzburg, Univ., Diss., 2000. / Zsfassung in dt. Sprache. - Auch als CD-Rom.

Thesis--Uppsala. / Summary in English. Includes index. Bibliography: p. 257-260.

Thesis (Ph. D.)--West Virginia University, 2010. / Title from document title page. Document formatted into pages; contains x, 170 p. : ill. (some col.). Includes abstract. Includes bibliographical references.

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1982. / Extra t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 96-103).

The Notch receptor is an evolutionarily highly conserved transmembrane protein essential to a wide spectrum of cellular systems. Notch is especially important to T-cell development, and its deregulation leads to leukemia. Although not well characterized, Notch signaling continues to play an integral role in peripheral T-cells, in which a unique mode of Notch activation can occur. In contrast to canonical Notch activation initiated by adjacent ligand-expressing cells, T-cell receptor (TCR)-stimulation is sufficient to induce robust Notch signaling. However, the interactions between these two pathways have not been defined. In this dissertation, we show that Notch activation occurs in peripheral T-cells within a few hours post TCR-stimulation and is required for optimal T-cell activation. Utilizing a panel of inhibitors against components of the TCR signaling cascade, we demonstrate that Notch activation is facilitated through initiation of protein kinase C-induced ADAM-metalloprotease activity. Moreover, internalization of Notch via endocytosis is indispensible for this process. Whereas ligand-mediated Notch stimulation relies on mechanical pulling forces that disrupt the autoinhibitory domain of Notch, we hypothesized that in T-cells in the absence of ligands, these conformational changes are induced through chemical adjustments in the endosome, causing alleviation of autoinhibition and receptor activation. Our data show that endocytosis is not only a prerequisite for TCR-induced Notch processing during normal T-cell function, but is essential even in Notch-mutated T-leukemia cells exhibiting constitutively active Notch signaling. Our work has also focused on signaling mechanisms of Notch following receptor activation. The Notch signal is transduced via cleavage of the intracellular portion of the receptor that subsequently translocates to the nucleus where it regulates gene transcription via interactions with its DNA-binding partner, RBPJκ. Utilizing RBPJκ-deficient T-cells, we show that, although Notch signaling is required, RBPJκ-dependent signaling is dispensable for peripheral T-cell proliferation and activation. Using retroviral constructs that encode modified, active forms of Notch restricted to the nucleus or cytoplasm, we provide evidence that Notch signaling may utilize RBPJκ-independent pathways for signal transduction. In conclusion, T-cells have evolved a unique method of Notch receptor activation, described for the first time in this dissertation, as well as novel mechanisms that facilitate downstream signaling.