Regulation of ErbB4 phosphorylation and cleavage by a novel histidine acid phosphatase.
Signaling by a variety of ligands including epidermal growth factor, betacellulin and neuregulin is mediated by the ErbB family of receptor tyrosine kinases. Studies on the prostate have shown that ErbB2 phosphorylation and signaling can be regulated by prostatic acid phosphatase, a histidine acid phosphatase which can dephosphorylate phospho-tyrosine residues in the ErbB2 receptor. Here we report that the histidine acid phosphatase ACPT (testicular acid phosphatase), which is highly homologous to the prostatic acid phosphatase, can dephosphorylate the ErbB4 receptor, which is known to play important roles in neuronal differentiation and synaptogenesis. ACPT and ErbB4 are both expressed in the brain where they are enriched at post-synaptic sites, and furthermore they can be co-immunoprecipitated from brain. We demonstrate that ACPT can inhibit basal and neuregulin-induced tyrosine phosphorylation of ErbB4. We also show that ACPT-dependent dephosphorylation can regulate the proteolytic cleavage of ErbB4, and this process can be reversed by applying the tyrosine phosphatase inhibitor, pervanadate. Furthermore, neuregulin-dependent differentiation of PC12 cells expressing ErbB4 is prevented by co-expressing ACPT. These results indicate that ACPT acts as a tyrosine phosphatase to modulate signals mediated by ErbB4 that are important for neuronal development and synaptic plasticity.
Fleisig
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H
The Graduate Program in Neuroscience, Department of Psychiatry, and the Brain Research Centre, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
El-Din El-Husseini
A
A
Vincent
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SR
D000135:Acid Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development*; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005333:Fetus; D020890:Neuregulin-1 / Q000378:metabolism / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000201:enzymology*; D016716:PC12 Cells; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D066247:Receptor, ErbB-4; D013347:Subcellular Fractions; D013570:Synaptic Membranes / Q000201:enzymology
D020890:Neuregulin-1; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D000135:Acid Phosphatase; C492298:Acp4 protein, rat; D017027:Protein Tyrosine Phosphatases; D010447:Peptide Hydrolases