In addition, a TG2/NFB positive feedback loop maintains TG2 expression and constitutive NFB activation [46,48,49]

In addition, a TG2/NFB positive feedback loop maintains TG2 expression and constitutive NFB activation [46,48,49]. cell death processes. This is often associated with mutation Methacycline HCl (Physiomycine) or overexpression of specific oncogenes that drive cancer cell survival, and/or silencing of tumor suppressor genes leading to enhanced cell division [1]. The fact that tumor cells proliferate at a higher rate than normal cells led to the design of cancer therapies that target rapidly proliferating cells. However, this approach has not been entirely satisfactory, as the cells often escape and become resistant. In this context, it has been realized that normal body tissues are derived from organ-specific stem cells that display a capacity to self-renew and to differentiate into the cell types that comprise the organ [2]. The cancer stem cell theory proposes that a small population of slow cycling, long-lived cancer cells, derived by mutation of normal stem cells, exist in tumors and are required for tumor Rabbit polyclonal to HDAC6 maintenance. This theory further suggests that the formation of a mutated stem cell is an early event in tumor formation. Increasing evidence suggests the cancer stem cells facilitate tumor formation, cancer recurrence, and metastasis [3C8], and resistance to conventional anti-cancer therapy [9]. An important recent goal in cancer biology is identification of therapeutic and preventive treatments that reduce cancer stem cell survival [10,11]. A key strategy in this context is identifying cancer stem cell survival proteins, that are either upregulated or display enhanced activity in cancer stem cells, as targets for anti-cancer prevention and therapy. In the present review, we discuss type II transglutaminase (TG2) as a marker of cancer development, as a cancer stem cell-survival protein, and as a potential anti-cancer stem cell prevention and therapy target. TG2 Structure and Activity TG2 is predominantly a cytosolic protein, but is also present in the nucleus, at the plasma membrane and Methacycline HCl (Physiomycine) in the extracellular environment [12,13]. As shown in Figure 1A, the TG2 sequence encodes an integrin- and fibronectin-binding N-terminal -sandwich domain, a catalytic core domain which includes the catalytic triad (Cys277, His335, and Asp358) that mediates TG2 crosslinking (transamidase) activity, and two C-terminal -barrel domains. The guanine nucleotide binding site, which encompasses part of -barrel1 and residues in the catalytic domain, is required for TG2-related signal transduction [14,15]. The TG2 GTP binding and the crosslinking functions have Methacycline HCl (Physiomycine) been heavily studied. Methacycline HCl (Physiomycine) In intact cells, where GTP/GDP levels are high and free calcium levels are low, TG2 exists in the GTP/GDP-bound closed/folded (signaling) conformation [12,16C19] (Figure 1B). If intracellular calcium levels rise, during cell death or in response to extracellular stimuli, calcium binding shifts TG2 to an open/extended crosslinking conformation which Methacycline HCl (Physiomycine) exposes the catalytic triad and activates proteinCprotein crosslinking (transamidase) activity [20]. This calcium-dependent change in conformation is associated with loss of GTP/GDP binding and related signaling (Figure 1B) [21C25]. The crosslinking activity of TG2 is allosterically activated by Ca2+ and inhibited by GTP, GDP, and GMP [26,27] (Figure 1B). Thus, the TG2 GTP-binding folded/closed (signaling) structure, and the open/extended (crosslinking) structure, are mutually exclusive. An additional mode of regulation involves oxidation of TG2 which converts the open/extended crosslinking-active form to the open crosslinking-inactive form, an event that is associated with oxidative conditions, particularly in the extracellular environment. We will argue that the TG2 closed (signaling) form is a major driver of cancer cell, and cancer stem cell survival. In addition, we suggest that the open (crosslinking) conformation can, in some contexts, enhance cancer cell survival, but that generally suppresses cell survival. We will review what is presently known in a range of cancer types. Open in a separate window Figure 1 TG2 structure and function. A: Schematic of TG2 showing the -sandwich, catalytic core, -barrel1, and -barrel2 domains, and the biological functions associated with each domain. Nucleotide binding (GTP/GDP) is mainly to residues from the first and last strands (amino acids 476C482 and 580C583) of -barrel.