SHP-2 Regulates Growth Factor Dependent Vascular Signalling and Function
Hanna Mannell and Florian Krotz
Affiliation: Invasive Cardiology, Clinic Starnberg, Oßwaldstr. 1, 82319 Munich, Germany.
Keywords: SHP-2, protein tyrosine phosphatase, Ptpn11, Noonans syndrome, PI3-K, MAPK, tyrosine phosphorylation, PTP,
N-SH2, endothelial cells.
Cellular responses to the environment are mediated by intracellular signalling pathways monitoring several
essential cellular processes, such as proliferation, migration, differentiation and survival. Cellular dysfunction is caused
by dysregulation of intracelleular signalling pathways and may ultimately result in pathophysiological conditions.
The non- transmembrane protein tyrosine phosphatase SHP-2 has been shown to be important for the control of cellular
behaviour. It influences the activity of several growth factor and cytokine dependent signalling pathways by association
with growth factor receptors, cell surface adhesion molecules and adaptor molecules such as Gab-1, Grb2 and IRS-1.
Upon FGF-2, EGF and insulin stimulation SHP-2 regulates MAPK pathway activation. In addition, SHP-2 is involved
in the regulation of cell survival by influencing the PI3-K/Akt pathway upon EGF, IGF and PDGF stimulation. Due to
these properties, SHP-2 function has recently gained more interest in vascular processes, such as in the differentiation
of cardiac progenitor cells and angiogenic events. Indeed, SHP-2 was shown to positively regulate endothelial cell
motility and angiogenesis in vitro and in vivo as well as controlling intracellular pH of endothelial and vascular smooth
muscle cells. On the other hand, SHP-2 was also demonstrated to be responsible for down regulation of VEGF receptor
2 activation upon dopamin and collagen stimulation. Finally, mutations in the Ptpn11 gene (encoding SHP-2) underlie
the developmental disorders Noonan syndrome and Leopard syndrome characterized by congenital heart disease and
hematologic abnormalities. Different mutations in this gene also result in myeloid and lymphoid malignancies. This
article summarizes the role of SHP-2 in signalling pathways relevant for vascular biology and associated disorders.
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