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.
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. The underlying signaling event(s) responsible for these aberrations are currently being elucidated. An important aspect that has not yet been determined is whether tumor metastasis is affected or not by the absence of Shb and this will be studied.
The absence of Shb exerts effects on hematopoiesis and peripheral T lymphocyte function. The blood profile demonstrates fewer macrophages and we are currently exploring the bone marrow events responsible for this. CD4+ T lymphocytes show a Th2 skewing of their response to stimulation in the absence of Shb and this could be of relevance for understanding allergic responses.
Finally, 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. Since Shb is only highly conserved among mammals with a true placenta, our intention is to assess the role of Shb in placenta formation.
Dissertations 2007 - 2011:
Nina Funa (2008)
Björn Åkerblom (2009)
For further information about this research group please contact Professor Michael Welsh: Michael.Welsh@mcb.uu.se