SHP2 and SIRP modulate erbB signals in astrocytes

University Of Pennsylvania, Philadelphia PA

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Abstract

This proposal is a renewal of studies aimed at determining molecular features and signaling properties of human astrocytomas, human brain tumors that are highly refractory to contemporary clinical management. EGFR (Epidermal Growth Factor Receptor)/erbB signaling has been shown to be critical for the transformed phenotype of particular subtypes of human astrocytoma. The goal of our laboratory is to better understand the role of the EGFR/erbB signaling system in astrocyte transformation. We have focused on mechanisms by which the SHP2 protein tyrosine phosphatase (FTP) and the SIRP inhibitory adhesion receptor modulate EGFR/erbB signals in normal and transformed astrocytes. Work performed during the present funding period demonstrates that SHP2 is a critical regulator of PI3-K and MAPK activation upon engagement of EGFR and that the SHP2 interaction with the Gab1 adaptor is required for positive signaling. Furthermore, we have shown positive coupling between SHP2 and EGFR and have observed an essential role for SHP2 PTPase activity in EGFR signaling and in maintaining oncogenic transformation mediated by the naturally occurring EGFRvlll oncoprotein. Our work has revealed that the EGFR signaling module involves an SHP2/Gab1/NFicB activation loop that is antagonized by the SIRP receptor through its sequestration of the SHP2/Gab1 complex. We have characterized additional attenuating mechanisms in EGFR signaling involving SHP2 and SIRP and have shown that these mechanisms are distinctly different from inhibition of EGFR with kinase-defective erbB receptors. Collectively, our model shows that SHP2 is the integrator of the EGFR and SIRP receptor systems and appears to be a critical switch in determining positive or negative signaling events in astrocyte growth and transformation. The next grant cycle will allow for further mechanistic studies, as well as translation and confirmation of our experimental findings. New therapeutic targets identified during the present funding period will be tested. In particular, a rodent brain tumor model will be used to evaluate inhibition of EGFR signaling components by MRI techniques. In parallel, human brain tumor tissue banked and archived in the laboratory of the PI will be used to validate our experimental model. The PI will obtain region-specific biopsies of human brain tumor tissue using MR image-guided techniques in surgical resection for these confirmatory studies. MR imaging methods used to diagnose and evaluate the biology of human tumors will be used for image-guided biopsies. Collectively, these efforts will further characterize potential treatment strategies that may ultimately improve therapeutic efforts for human astrocytomas.