Importance of Shb-dependent signaling for glucose homeostasis, angiogenesis, hematopoiesis and reproduction.
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.
We observe impaired glucose homeostasis due to insufficient insulin secretion in the absence of Shb. In addition, the beta-cells exhibit reduced stress sensitivity. These effects on beta-cells are at least partly due to deregulated focal adhesion kinase signaling.
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.
Shb-knockout mice also display reduced angiogenesis and this causes diminished tumor expansion (subcutaneously injected tumor cells or inheritable RIP-Tag insulinomas). Endothelial cells without Shb have an abnormal cytoskeleton and adherens junctions that may contribute to deficient angiogenesis. In addition, Shb-knockout vascular physiology shows signs of compensatory mechanisms (increased blood flow and an increased frequency of intermediately sized arterioles as determined by micro-CT) to counteract the adverse effects of the endothelial dysfunction. These aberrations are not due to regulatory roles of myeloid cells but reflect an inherent impairment of the vasculature. The Shb-knockout vasculature also confers increased metastasis of B16F10 melanomas due to increased vascular leakage and reduced recruitment of CD8+ cytotoxic T cells.
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.
Hematopoietic stem cells show less proliferation in the absence of Shb due to elevated focal adhesion kinase activity. When examining BCR-ABL1-induced myeloid leukemia is the absence of Shb, a more severe disease disease developed. Again, this phenotype appeared to result from increased activity of focal adhesion kinase.
Dissertations 2007 - 2014:
Nina Funa (2008)
Björn Åkerblom (2009)
Karin Gustafsson (2013)
For further information about this research group please contact Professor Michael Welsh: Michael.Welsh@mcb.uu.se