Protein tyrosine phosphatases (PTPs) dephosphorylate inhibitory or activating sites in kinases or their substrates, and hence can respectively act in synergism or in antagonism with kinase activation. RPTPa is a typical """"""""receptor' (trans-membrane) PTP, which overexpression studies have implicated in regulation of Src family kinases, cell adhesion and transformation, various neuronal functions, and insulin sensitivity. RPTPCL can be regulated by PKC-induced serine phosphorylation, by tyrosine phosphorylation of its C-terminus (and ensuing association with the adaptor Grb2), by dimerization, and by ectodomain-mediated interactions. It was recently shown that RPTPa inactivation by homologous recombination results in reduced activity of the Src family kinases (SFKs) c-Src and Fyn, and ensuing deficiencies in integrin-dependent responses. We wish to investigate to what extent the requirement for RPTPa in Src activation affects cellular responsiveness to PDGF as a model growth factor acting through a receptor tyrosine kinase, in terms of downstream signaling pathways, mitogenesis and chemotaxis. RPTPa-/- animals display anatomical abnormalities in various brain regions, and abnormally high astrocyte numbers. The proposed studies will address whether the RPTPa-/- phenotype reflects defective neuronal migration and/or survival, and whether the hyperabundance of astrocytes is developmental, or reflects reactive gliosis. As a first step to understand the molecular mechanism(s) behind these phenotype(s), genetic experiments will be performed to test whether or not an effect of RPTPa cn Src family kinases is involved. Lastly, studies will be performed aimed at identifying additional substrates for RPTPa. These will be accompanied by specific tests of models regarding regulation of RPTPa activity by dimerization, and the role of tyrosine phosphorylation of RPTPa in controlling its substrate specificity. Several lessons drawn from the study of this PTP may be relevant to our understanding of the PTP family in general.
| Vacaresse, Nathalie; Moller, Bente; Danielsen, E Michael et al. (2008) Activation of c-Src and Fyn kinases by protein-tyrosine phosphatase RPTPalpha is substrate-specific and compatible with lipid raft localization. J Biol Chem 283:35815-24 |
| Petrone, Angiola; Battaglia, Fortunato; Wang, Cheng et al. (2003) Receptor protein tyrosine phosphatase alpha is essential for hippocampal neuronal migration and long-term potentiation. EMBO J 22:4121-31 |
