Negative regulation of cytokine signalling is essential for maintaining hematopoietic homeostasis. We investigated the role of SH2B1 and CBL in the negative regulation of EPO and GM-CSF signaling, respectively. Erythropoiesis is driven by the cytokine erythropoietin (EPO), which mediates its signal by binding to its cognate receptor, the erythropoietin receptor (EPO-R). Murine knock-in studies have demonstrated EPO-R Tyr343 to play an important role in EPO mediated signalling. We have utilized a Cloning of Ligand Target (COLT) screen to identify the adaptor protein SH2B1 as an interactor of EPO-R pTyr343. We have demonstrated that SH2B1 binds to EPO-R via two mechanisms. The amino-terminus of SH2B1 and the membrane proximal region of EPO-R mediate SH2B1 constitutive binding to EPO-R. SH2B1 binds to EPO-R pTyr343 and pTyr 401 in an SH2 domain-dependent manner. SH2B1 displayed dose- and time- dependent Serine/Threonine phosphorylation in response to EPO stimulation. Knockdown of SH2B1 resulted in enhanced activation of Jak2 and EPO-R. These studies demonstrate SH2B1 as a novel negative regulator of EPO signalling. Mutations in the linker region and the RING finger of CBL have been identified in a number of myeloid malignancies, including juvenile myelomonocytic leukemia. We investigated how linker region mutant, CBL-Y371H, and RING finger mutant, CBL-C384R lead to GM-CSF hypersensitivity. Expression of these CBL mutants in the human hematopoietic cell line, TF-1, showed enhanced stimulation induced phosphorylation of GM-CSFR βc. We also demonstrated that the loss of E3 ligase activity of these CBL mutants results in increased expression of JAK2 and LYN kinases. Assessment of the effects of CBL mutants on downstream signalling revealed enhanced phosphorylation of SHP2, CBL and S6. Dasatinib induced inhibition of SRC family kinases abolished the elevated phosphorylation of CBL mutants, and equalized the phosphorylation of GM-CSFR βc in the wild type and CBL mutant cells.

Bibliography: leaves 91-126. / xiv, 126, [61] leaves, [13] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Studies the in-vitro characterisation of residual normal stem cells in the bone marrow (BM) and peripheral blood (PB) at diagnosis in chronic myloid leukaemia (CML). Shows that both the CD34+DR- populations of blood and marrow of patients in early chronic phase CML contain BCR-ABL- preprogenitors and are potential targets for positive selection in an autologous transplant program. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1998

Bibliography: leaves 91-126. / xiv, 126, [61] leaves, [13] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Studies the in-vitro characterisation of residual normal stem cells in the bone marrow (BM) and peripheral blood (PB) at diagnosis in chronic myloid leukaemia (CML). Shows that both the CD34+DR- populations of blood and marrow of patients in early chronic phase CML contain BCR-ABL- preprogenitors and are potential targets for positive selection in an autologous transplant program. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1998

"Research conducted at the Department of Haematology, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science."--T.p. / Includes bibliographical references (leaves 170-214). / xiv, 221 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Elevated levels of receptor tyrosine kinases have been implicated in carcinogenesis. It is possible that high expression of c-Kit by the leukaemic cell provides them with a growth advantage over their normal counterparts in the bone marrow microenvironment. Thus, a means of inhibiting the interaction of c-Kit on these cells with ligand Steel Factor may remove proliferation and survival signals. Main aim of the study was to produce a biological inhibitor of this interaction and evaluate its ability to prevent ligand Steel Factor from binding to c-Kit on live cells. / Thesis (Ph.D.)--University of Adelaide, Dept. of Molecular Biosciences, 2001

Thesis (Ph.D.)--Ohio University, August, 2007. / Title from PDF t.p. Includes bibliographical references.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Adelaide, Dept. of Medicine, 1998. / Includes bibliographical references (leaves 91-126).

Thesis (Ph.D.) -- University of Adelaide, Dept. of Molecular Biosciences, 2001. / "Research conducted at the Department of Haematology, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science."--T.p. Includes bibliographical references (leaves 170-214).

Thesis (M. Phil.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 126-137).

Thesis (M. Phil.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.