The overall aims of our studies are to increase our understanding of leukemia progression and solid tumor metastasis by usage of the Shb-gene knockout model. These tumor processes will in particular be related to immune cell responses. The project involves both in vivo and in vitro experimentation and in an extension it is hoped that small molecular weight inhibitors of Shb function can be found that have an application in medicine.
The Shb gene in tumor biology.
Shb is an SH2-domain adapter protein operating downstream of tyrosine kinase receptors such as the VEGFR-2, FGFR-1, PDGF-receptors and the T cell receptor. The effects of Shb are pleiotropic and context dependent. We have recently generated a Shb-knockout mouse to assess the physiological relevance of Shb in vivo.
Shb-knockout mice display reproductive abnormalities with a transmission ratio distortion of the knockout allele related to female reproduction. Consequently, oocyte maturation is impaired in the absence of Shb and this relates to abnormal signaling via the ERK-RSK-S6 pathway. In addition to aberrant oocyte maturation, Shb-knockout embryos are morphologically abnormal and do not implant well.
The absence of Shb exerts effects on hematopoiesis and peripheral T lymphocyte function. CD4+ T lymphocytes show a Th2 skewing of their response to stimulation in the absence of Shb and this confers increased allergic responses.
Current efforts aim at understanding the role of Shb in hematopoietic malignancies and how it affects immune surveillance against tumor cells.