Biochem. J. (2011) 439, 195–205 (Printed in Great Britain) doi:10.1042/BJ20110903 195 REVIEW ARTICLE PDZ domains: the building blocks regulating tumorigenesis Vanitha Krishna SUBBAIAH 1 , Christian KRANJEC 1 , Miranda THOMAS and Lawrence BANKS 2 International Centre for Genetic Engineering and Biotechnology, Padriciano 99, I-34012 Trieste, Italy Over 250 PDZ (PSD95/Dlg/ZO-1) domain-containing proteins have been described in the human proteome. As many of these possess multiple PDZ domains, the potential combinations of associations with proteins that possess PBMs (PDZ-binding motifs) are vast. However, PDZ domain recognition is a highly specific process, and much less promiscuous than originally thought. Furthermore, a large number of PDZ domain-containing proteins have been linked directly to the control of processes whose loss, or inappropriate activation, contribute to the development of human malignancies. These regulate processes as diverse as cytoskeletal organization, cell polarity, cell proliferation and many signal transduction pathways. In the present review, we discuss how PBM–PDZ recognition and imbalances therein can perturb cellular homoeostasis and ultimately contribute to malignant progression. Key words: cancer, cell invasion, cell polarity, PDZ domain, tumour virus. INTRODUCTION The PDZ domain-containing family of proteins were first recognized in the early 1990s and were classified as such, by having stretches of amino acids in common with the first such members to be identified, PSD95 (postsynaptic density protein 95), Dlg (discs large) and ZO-1 (zonula occludens protein 1), hence the origin of the name [1]. They are found from bacteria to vertebrates [2] and are involved in an extremely large number of activities within the cell, including control of cell migration and invasion, cell proliferation, cell polarity, cell attachment and cell–cell contact, apoptosis and immune cell recognition and signalling. PDZ domains themselves are sites of protein–protein interaction, and, as many of these proteins have multiple PDZ domains capable of multiple protein interactions, they are generally considered, somewhat simplistically, to act as scaffolding molecules, around which multi-protein signalling complexes are assembled. Before discussing how PDZ domain-containing proteins might affect tumorigenesis, we need to consider the molecular basis for PDZ domain recognition. It is often impossible to separate the functions of PDZ domain proteins from those of their ligands that possess PBMs (PDZ-binding motifs). Therefore one must always remember that this is a two-way interaction where, for example, the PDZ domain-containing protein may exert tumour- suppressor activity by regulating the activity of a PBM-containing ligand, such as Scribble with β -Pix [3]. Conversely, a PBM ligand may act directly on, and inactivate or sequester, a PDZ domain- containing partner, for example, the interaction between the HPV (human papillomavirus) E6 oncoprotein and Dlg [4]. STRUCTURAL BASIS OF PDZ–PBM RECOGNITION PDZ domains are regions of usually 80–90 amino acid residues, all having certain defining structural elements: six β -sheets (β A– β F) and two α-helices, one short (αA) and one long (αB) [5–7]. These are shown as a cartoon in Figure 1(A), aligned with each of the three PDZ domains of human Dlg1. Although there is considerable variation in the length and structure of the linking sequences, these conserved elements form a highly conserved fold, which contains the carboxy-binding loop, between the β A and β B sheets [5,6]. This is the so-called GLGF motif, actually R/K-X-X-X-G--G- where X is any residue and  is a hydrophobic residue; the side chains of these residues form the hydrophobic pocket that provides the binding activity of PDZ domains [5,8]. In fact, apart from the totally conserved second glycine residue, the exact residues forming the GLGF motif can vary quite significantly and thus contribute to binding specificity. The canonical PDZ-binding domains fold to bring the N- and C- termini of the domain close together at the ‘back’ of the structure, while the binding groove is formed by the β B sheet and αB helix, with the GLGF motif at the end, reminiscent of the contact point in an electric socket. The shape of a correctly folded PDZ domain is shown in Figure 1(B), based on the crystal structure of the Dlg PDZ domain 2 [7]. It has been shown in the PDZ2 domain of PSD95, that the loop connecting the β A and β B sheets (which contains the GLGF motif), and the loop connecting the αB helix and β F sheet both retain flexibility in solution, whereas the remainder of the structure is relatively rigid [9]. It is easy to envisage that the flexibility of the loops could allow the rigid elements to move relative to one another, facilitating the insertion Abbreviations used: AF-6, ALL1-fused gene from chromosome 6; APC, adenomatous polyposis coli; aPKC, atypical protein kinase C; Bcr, breakpoint cluster region; CADM1, cell adhesion molecule 1; Cdc42, cell division cycle 42; Daam1, Dishevelled-associated activator of morphogenesis 1; Dlg, discs large; Dvl, Dishevelled; EMT, epithelial–mesenchymal transition; ERK, extracellular-signal-regulated kinase; FAP-1, Fas-associated phosphatase 1; GEF, guanine-nucleotide-exchange factor; GIPC1, GAIP (G α -interacting protein)-interacting protein C-terminus 1; HPV, human papillomavirus; HTLV-1, human T-cell leukaemia virus type 1; IGF-1, insulin-like growth factor 1; LARG, leukaemia-associated Rho-GEF; LNX1, Ligand of Numb protein X1; MAGI, membrane-associated guanylate kinase with inverted domain structure; MyoGEF, myosin-interacting GEF; NHERF-1, Na + /H + -exchanger regulatory factor 1; Par, partitioning defective; PBM, PDZ-binding motif; PDZ, PSD95/Dlg/ZO-1; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PSD95, postsynaptic density protein 95; PTEN, phosphatase and tensin homologue deleted on chromosome 10; PTP, protein tyrosine phosphatase; RhPV, rhesus papillomavirus; RIL, reversion-induced LIM protein; ROCK, Rho-associated kinase; S1P, sphingosine 1-phosphate; S1P1, S1P receptor 1; Smurf1, Smad ubiquitylation-regulatory factor 1; Tiam1, T-cell lymphoma invasion and metastasis 1; TJ, tight junction; TRIP6, thyroid receptor-interacting protein 6; ZO, zonula occludens protein. 1 These authors contributed equally to this review. 2 To whom correspondence should be addressed (email Banks@icgeb.org). c  The Authors Journal compilation c  2011 Biochemical Society