Physiological and Pathological Roles of Tissue Plasminogen Activator and Its Inhibitor Neuroserpin in the Nervous System
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector MINI REVIEW published: 13 October 2015 doi: 10.3389/fncel.2015.00396 Physiological and pathological roles of tissue plasminogen activator and its inhibitor neuroserpin in the nervous system Tet Woo Lee 1 †, Vicky W. K. Tsang 1 and Nigel P. Birch 1, 2* 1 School of Biological Sciences and Centre for Brain Research, University of Auckland, Auckland, New Zealand, 2 Brain Research New Zealand, Rangahau Roro Aotearoa, Auckland, New Zealand Although its roles in the vascular space are most well-known, tissue plasminogen activator (tPA) is widely expressed in the developing and adult nervous system, where its activity is believed to be regulated by neuroserpin, a predominantly brain-specific member of the serpin family of protease inhibitors. In the normal physiological state, Edited by: tPA has been shown to play roles in the development and plasticity of the nervous Daniel A. Lawrence, system. Ischemic damage, however, may lead to excess tPA activity in the brain University of Michigan Medical School, USA and this is believed to contribute to neurodegeneration. In this article, we briefly Reviewed by: review the physiological and pathological roles of tPA in the nervous system, which Linda Fredriksson, includes neuronal migration, axonal growth, synaptic plasticity, neuroprotection and Karolinska Institutet, Sweden Maria Elena Miranda Banos, neurodegeneration, as well as a contribution to neurological disease. We summarize Sapienza University of Rome, Italy tPA’s multiple mechanisms of action and also highlight the contributions of the inhibitor *Correspondence: neuroserpin to these processes. Nigel P. Birch, School of Biological Sciences, Keywords: serine protease, serpin, neuronal migration, neurite growth, synaptic plasticity, neurodegeneration and University of Auckland, Private Bag neuroprotection, Alzheimer’s disease, neurovascular unit 92019, Auckland 1142, New Zealand [email protected] †Present Address: Introduction Tet Woo Lee, Department of Anatomy, University of Research of tissue plasminogen activator (tPA) in the nervous system has linked this protease to Otago, Dunedin, New Zealand a number of functions, including cell migration, axonal growth, and synaptic plasticity, as well as a contribution to neurodegeneration in pathological states. The main inhibitor of plasminogen Received: 28 July 2015 activator proteolytic activity in the vascular space is the serpin plasminogen activator inhibitor Accepted: 22 September 2015 1 (PAI-1; SERPINE1). This serpin, however, is only weakly expressed in the brain (Sawdey and Published: 13 October 2015 Loskutoff, 1991; Masos and Miskin, 1997). Another serpin, protease nexin-1 (PN-1; SERPINE2) is Citation: expressed throughout the brain (Sappino et al., 1993; Reinhard et al., 1994). Although PN-1 may Lee TW, Tsang VWK and Birch NP play some role in regulating tPA activity (Kvajo et al., 2004; Samson et al., 2008), its inhibitory (2015) Physiological and pathological kinetics suggest that it mainly functions as inhibitor of thrombin (Scott et al., 1985). Instead, the roles of tissue plasminogen activator and its inhibitor neuroserpin in the predominant inhibitor of neuronal tPA activity is believed to be the neuroserpin (SERPINI1), a nervous system. serpin that is largely specific to the nervous system (Osterwalder et al., 1996; Hastings et al., 1997; Front. Cell. Neurosci. 9:396. Krueger et al., 1997). This review will focus on the interplay of these two players in the nervous doi: 10.3389/fncel.2015.00396 system (Figure 1). Frontiers in Cellular Neuroscience | www.frontiersin.org 1 October 2015 | Volume 9 | Article 396 Lee et al. Roles of tPA and neuroserpin B tPA: plasminindependent proteolytic mechanisms C tPA: nonproteolytic mechanisms SP ND NP cleavage? / interaction with potentiation of transctivation of Trk receptors NG NMDA subunits NMDA signaling induction of MMPs ND NG NV formation of complexes with other serpins (e.g. PAI-1) macrophage recruitment ND NG activation of PDGF-CC and NG PDGFRα signaling NV annexin II LRP receptor receptor activation NG ND of MMPs unknown mechanism CA NG interaction with amyloid beta? AD co-factor + unknown activation of plasmin NP tPA active neuroserpin E neuroserpin: noninhibitory eects neurotrophin processing NG ? SP AD clearance of amyloid beta tPA:neuroserpin & induced MMPs induced & complex breakdown of CM ? NG ND ECM components D transient inhibition of tPA proteolytic activity A tPA: plasmindependent mechanisms possible cleaved neuroserpin biological function? cellular eects: CM cell migration NG neurite growth CA cell-cell adhesion SP synaptic plasticity ND neurodegeneration NP neuroprotection NV neurovascular permeability AD involvement with Alzheimer’s disease FIGURE 1 | Schematic summarizing the pleotropic roles of tPA in the nervous system and its interaction with the inhibitor neuroserpin. While tPA is named for its function to proteolytically activate the zymogen plasminogen to plasmin (A), it can also act on other substrates in a plasmin-independent manner (B). In addition, tPA can bind to cell-surface receptors and act via non-proteolytic mechanisms (C), although binding to the LRP receptor in particular is affected by formation of complexes of tPA with serpin partners, which requires the proteolytic activity of tPA. The proteolytic activity of tPA can be inhibited by neuroserpin (D), although tPA:neuroserpin complexes are unstable and this inhibition is only transient. There is also evidence of neuroserpin having non-inhibitory effects (E) although the mechanism of these is unknown. The main molecular events for each mechanism are indicated; the icons indicate the cellular effects associated with these molecular events. Effects for which there is only limited evidence are shown with a question mark. Neuroserpin as an Inhibitor of tPA and active tPA (Barker-Carlson et al., 2002; Ricagno et al., 2009; Lee et al., 2015). As complex dissociation is expected to occur Analysis of neuroserpin sequence indicated that it was likely prior to clearance (Barker-Carlson et al., 2002), these data suggest to be an inhibitor of trypsin-like serine proteases (Osterwalder that neuroserpin is likely to function as a transient inhibitor of et al., 1996). Biochemical evidence subsequently showed tPA in vivo. Interestingly, evolutionarily conserved residues in strong inhibition of tPA by neuroserpin and considerably less neuroserpin regulate the half-life of tPA:neuroserpin complexes, efficient inhibition of urokinase plasminogen activator (uPA), suggesting that the precise half-life of the complexes may be trypsin, NGF-γ, plasmin, and thrombin (Hastings et al., 1997; physiologically important (Lee et al., 2015). tPA:neuroserpin Osterwalder et al., 1998). The function of neuroserpin as an interactions may involve other players, such as an unknown inhibitor of tPA is supported by their similar expression patterns co-factor that stabilizes the complex (Barker-Carlson et al., in the nervous system (Hastings et al., 1997; Krueger et al., 1997; 2002). Neuroserpin’s weak inhibition of other proteases, such as Teesalu et al., 2004) and data showing that tPA activity levels are plasmin, may also be physiological important (Wu et al., 2010) decreased by over-expression of neuroserpin in the brain (Cinelli and it is also possible that neuroserpin may have other protease et al., 2001). targets that have not yet been determined. There is evidence Other results, however, indicate that neuroserpin does not of non-inhibitory functions of neuroserpin (Lee et al., 2008), behave as a classical inhibitory serpin toward tPA. Unlike most raising the alternate possibility that tPA modulates neuroserpin covalent serpin:protease complexes, tPA:neuroserpin is unstable activity by cleaving neuroserpin to produce a form with distinct and dissociates within minutes to release cleaved neuroserpin (non-inhibitory) biological activity. Frontiers in Cellular Neuroscience | www.frontiersin.org 2 October 2015 | Volume 9 | Article 396 Lee et al. Roles of tPA and neuroserpin Expression of Neuroserpin and tPA in the over-expression causes increased neurite outgrowth (Pittman Nervous System and Dibenedetto, 1995; Baranes et al., 1998; Lee et al., 2007a). Similarly, altered expression of neuroserpin has been shown to Both tPA and neuroserpin are expressed in neurons throughout trigger changes in the extension of neurite-like processes of AtT- the developing and the adult nervous systems (Sappino et al., 20 cells (Hill et al., 2000) and NGF-mediated neurite outgrowth 1993; Friedman and Seeds, 1994; Ware et al., 1995; Osterwalder in PC12 cells (Parmar et al., 2002; Navarro-Yubero et al., 2004). et al., 1996; Krueger et al., 1997; Teesalu et al., 2004), with A role of tPA in axonal growth has also been shown in vivo. spatial and temporal expression patterns suggesting roles in In one study, tPA-knockout mice show abnormal growth of neuronal migration, axonal growth, synaptic development, mossy fiber axons in the dentate gyrus following seizure (Wu neuronal plasticity and regulation of neurovascular responses. et al., 2000). Other reports have focused on the role of tPA in High neuroserpin expression has been shown in post-mitotic axonal regeneration following damage. In studies using the sciatic cells undergoing neurogenesis in the adult (Yamada et al., 2010), nerve crush model of peripheral nervous system regeneration, also suggesting a function in neuronal maturation.