Year: 2008
Type: dissertation
Abstract: Protein tyrosine phosphatase receptor type Z (Ptprz, also known as PTPζ or RPTPβ) is preferentially expressed in the brain as a major chondroitin sulfate proteoglycan.Three splicing variants, two receptor-type isoforms and one secretory isoform, are known.Ptprz interacts with the PSD95 family through its intracellular carboxyl-terminal PDZ-binding motif in the postsynaptic density of the adult brain.Ptprz-deficient mice display impairments in spatial and contextual learning.Here, I show that the extracellular region of the receptor isoforms of Ptprz are cleaved by metalloproteinases including ADAM-17 (TACE) and subsequently the membrane-tethered fragment is cleaved by presenilin/γ-secretase, releasing its intracellular region into the cytoplasm: Noteworthily, the intracellular fragment of Ptprz shows nuclear localization.Administration of GM6001, an inhibitor of metalloproteinases, to mice demonstrated the metalloproteinase-mediated cleavage of Ptprz under physiological conditions.Furthermore, I identified the cleavage sites in the extracellular juxtamembrane region of Ptprz by TACE and MMP-9.This is the first evidence of the metalloproteinase-mediated processing of an RPTP in the central nervous system.I also identified the proteolytic processing of Ptprz by plasmin in the adult mouse brain, which is markedly enhanced after kainate-induced seizures.We estimated the cleavage sites in the extracellular region of Ptprz based on cell-based assays and in vitro digestion experiments with recombinant proteins.The findings indicate that Ptprz is a physiological target for activity-dependent proteolytic processing by the tPA/plasmin system, and suggest that the proteolytic fragments are involved in the structural and functional processes of the synapses during learning and memory. 1 Chapter I General introduction 2 I.1 Regulation of protein phosphorylation Phosphorylation on protein is a fundamental mechanism for cell signaling.By changing the status of phosphorylation on protein, signals are transduced within cells.In particular, phosphorylation on tyrosine is extensively developed in multicellular eukaryotes.It is used to for many cellular events including, cellular mobility, proliferation and differentiation.It also plays role on the coordination of these processes among neighboring cells in embryogenesis, organ development, tissue homeostasis, and the immune system.Protein tyrosine phosphorylation is controlled by the balance between the activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs).Proportionally, much more researches have focused on PTKs in the last 20 years.It may be due to the historical reason that the first PTK (Czernilofsky et al., 1980) was cloned 10 years earlier than the first PTP (Guan et al., 1990).There exist 81 activePTPs and 85 active PTKs encoded by human genome (Tonks, 2006).From this similar amount, one can therefore assume that they have comparable significance in cellular signaling.In fact, recent findings have led to the recognition that PTPs play important and active roles in regulating the level of tyrosine phosphorylation. I.1.1 Receptor-like protein tyrosine phosphataseMembers of PTP super-family are characterized by the presence of a signature motif, Aloso et al., 2004).Based on the amino acid sequences of their catalytic domain, the PTPs can be divided into two classes: the classical phosphotyrosine (pTyr)-specific phosphatases and the dual specificity phosphatases (for both phosphothreonine and phosphotyrosine).There are 8 subtypes of receptor-like
Authors: Pakhong Jeremy Chow, パク ホンジェレミー チョウ
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W780831428