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An ErbB4 regulating novel acid phosphatase implicated in neuronal development Fleisig, Helen

Abstract

Maintaining homeostasis or responding to cellular stimuli requires an intricate network of proteins that are capable of communicating and working in concert. Kinases and phosphatases are key participants in this network. Most frequently functioning as "on" and "off switches for signaling cascades, they are regulators of physiological processes that determine the phosphorylation state of receptors, phospholipids, metabolites and other proteins. Histidine acid phosphatases comprise a family of enzymes that achieve optimal catalytic activity at an acidic pH, in vitro. They include prostatic (PAP), lysosomal and lysophosphatidic acid phosphatases. In this study, a novel histidine acid phosphatase (ACPT), that is highly homologous to PAP, was cloned and characterized. RT-PCR studies indicated that ACPT has a wide tissue distribution and within the brain, it is highly expressed in the cortex, hippocampus and striatum, as indicated by antibodies generated specifically against ACPT. This distribution pattern is notably different from PAP in that it is present in the brain, whereas PAP is absent. ACPT was found to be enriched at post-synaptic sites and immunocytochemical studies of hippocampal neurons revealed coexpression of the enzyme with synaptic proteins. Recently, PAP has been shown to regulate the function of ErbB2, a member of the epidermal growth factor (EGF) family of receptor tyrosine kinases. Using immunoprecipitation studies, it was found that ACPT associates with ErbB4, a member of the EGF receptor family that is enriched in the brain. It was also demonstrated that this interaction results in regulation of ErbB4 function when ACPT acts as a tyrosine phosphatase ' and consequently influences receptor cleavage. The differentiation of PC 12 cells induced by ErbB4 activation can be prevented by the expression of ACPT. Although this neurite outgrowth is mediated by the same MAP kinase pathway which is responsible for nerve growth factor (NGF) induced-trk-dependent differentiation, the phosphatase regulation is ErbB4 specific. Therefore, ACPT may participate in neuronal differentiation through its regulation of the ErbB4 receptor.

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