Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126 Review Review Peptidyl-prolyl isomerase (PPIase): an emerging area in tumor biology Pulak Ranjan Nath1* 1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. *Corresponding author: *Corresponding author: Dr. Pulak Ranjan Nath, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20812, USA. Tel:+1 (301) 480 4353, Fax:+1 (301) 480 0611; E-Mail: [email protected] or [email protected] Citation: Pulak Ranjan Nath. Peptidyl-prolyl isomerase (PPIase): an emerging area in tumor biology. Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126 Copyright: @ 2017 Pulak Ranjan Nath. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Competing Interests: The author declares no competing financial interests. Received May 5, 2017; Revised Sept 10, 2017; Accepted Oct 2, 2017. Published Nov 6, 2017 Abstract Peptidyl-prolyl isomerase (PPIase) catalyzes the interconversion of a specific Pro-imide bond between the cis and trans conformations. Such conformational interconversion by PPIases at the backbone of key signaling proteins is an emerging area of active research. Two families of PPIases, cyclophilins and FK506-binding proteins (FKBPs), have been extensively studied due to their high affinity for immunosuppressive drugs, cyclosporine A and FK506, respectively. These two families of PPIases and also Pin1 within the parvulin-family mediate temporal and spatial conformational modifications of signaling proteins; therefore, affecting the downstream signaling events. PPIases have recently been implicated in multiple aspects of cell cycle regulation and cellular processes related to a number of human pathologies, including cancer. This review highlights the causal relationship between PPIases and malignant transformation and progression. Based on the current understanding, it is postulated that a cancer intervention strategy based on the development of isomerase-specific inhibitors is not far away. Keywords: PPIases, Cyclophilin, FKBP, Pin1 Posttranslational protein modifications not only increase in the diversity of the proteome, but serve Introduction also as efficient mechanisms for temporal and spatial A properly folded protein under physiological regulation of activity in many types of effector conditions must maintain its functional integrity as a molecules. Among the most common mechanisms of part of the entire proteome. Pathophysiological protein modifications, peptidyl-prolyl cis–trans alterations, such as malignancy, have been shown to isomerization, mediated by a family of enzymes remodel folding-mediated signaling pathways. termed as PPIases, has been a topic of active research. Typically, certain peptide bonds on the backbone of a PPIase includes a large number of highly conserved native protein can adopt cis/trans isomerism, which proteins, which are widely distributed throughout resembles a molecular switch for bioactivity (1). Any organisms. These are structurally related proteins and alteration of the productive folding and restructuring share an isomerization domain [Fig. 1]. PPIases are pathways may result in misfolded and dysfunctional also found to be overexpressed in a variety of human proteins that are implicated to play critical role in tumors [Fig. 2, Table 1], and are implicated to play malignancy (2). Distinct posttranslational modification critical role in tumor generation and progression. mechanisms involving a large number of proteins The unique property of PPIases (EC 5.2.1.8) attributes tightly regulate cell growth and differentiation. to their ability to modify protein structure by cis– - 126 - Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126 Review Table 1. List of human cancers that exhibit overexpression of specific family of PPIases. Cyclophilins Ref. FKBPs Ref. Pin1 Ref. Glioma 50 CLL 71 Melanoma 112,113 Myeloma 49 Glioma 84 Lung cancer 107,112,113 Melanoma 57 Melanoma 85,89 Ovary cancer 112,113 Lung cancer 34 Astrocytoma 70 Breast cancer 112,113 Brain tumor 34 Glioblastoma 27, 73 Cervical tumor 112,113 Breast cancer 34,53 Breast cancer 95,96,105 Oral carcinoma 98,110,111 Uterus cancer 53 Retinal tumor 90 Prostate cancer 108,109 Ovarian cancer 53 Prostate cancer 53,101 Esophageal 110 Prostate cancer 39,53 Colorectal cancer 102 carcinoma Adenocarcinoma 42 Cervical neoplasia 78 Esophageal cancer 43 B-cell lymphoma 75 Endometrial carcinoma 36 Epithelial carcinoma 82 Hepatocellular 34,40 Hepatocellular carcinoma 99 carcinoma trans-isomerization of peptide bonds preceding to a enzymatic domains [Fig. 1], suggesting a broad specific proline residue. Though, a trans (ω = 180◦) substrate specificity and functional redundancy (21). conformation is energetically favored, below 10% of Cyps and FKBPs, also known as ‘immunophilins’, have the newly synthesized proteins containing a peptidyl- high binding affinity for the immunosuppressive drugs prolyl bond, acquire a cis (ω = 0◦) conformation during cyclosporine A (CsA) and FK506, respectively (22). normal physiological processes in the eukaryotes. The Immunophilins were initially identified as molecular high-energy barrier between the cis and trans states chaperones (20) though their isomerization-based role (3) mostly limits a spontaneous cis–trans protein in folding of nascent proteins was appreciated. interconversion (4-6). Thanks to an active PPIase, Immunophilins interact with calcineurin at the basal which greatly reduces the free energy requirement level, however the affinity of such interaction and accelerates the interconversion of protein states increases upon binding of CsA and FK506. (7-9) and results in more biologically meaningful Immunophilin-calcineurin interaction results in the consequences. Recently, we have shown that PPIases inhibition of calcineurin to activate NF-AT (23) and play important role in T cell signaling pathways by subsequent transcription of the IL-2 gene (24) altering conformational regulation of adaptor protein CrkII survival and differentiation of CD4+ and CD8+ T cells (10-12). However, controversies on the true catalytic (25). We have recently discussed the molecular mechanism driving cis–trans isomerization are still pathways that are affected by the CsA-Cyp and FK506- prevalent (13-17). FKBP interactions elsewhere (21). Members of the PPIases are grouped into three subfamilies: third subfamily of PPIases, parvulins including Pin1, cyclophilins (Cyps), FK506 binding protein (FKBPs), and are structurally and functionally distinct from Cyps or parvulins (18-20). We have recently listed several FKBPs. Unlike the immunophilins, the catalytic activity distinct functional proteins of Cyps, FKBPs and of Pin1 is kinase activation-dependent and isomerizes parvulins that play an important role in immune cells, phospho-serine/threonine-proline motif-containing cellular localization and chromosomal locations of proteins. The role of immunophilins and Pin1 in the encoding genes (21). We found that the prototypic regulation of immune cell functions and their members of PPIase families, CypA, FKBP12 and Pin1 involvement in the regulation of other normal and are ubiquitously expressed in mouse organs and pathological cellular functions have recently been tissues [Fig. 3]. Interestingly, members of three discussed elsewhere (21,26-29). This review takes a families of PPIases share conserved regions within - 127 - Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126 Review Schematic Schematic n n numbers that that are involved in tumor growth dues that border the protein domains or modules modules or domains protein the border that dues member member proteins - recognition recognition motif; TPR, tetratricopeptide repeat; EF, EF hand; WD40, Prot, Pfam or ClustalW alignment. The PPIase domain is indicated in red. Functionally important important Functionally red. in indicated is domain PPIase The alignment. ClustalW or Pfam Prot, - Prot database and NCBI Reference Sequence are given. Amino acid resi acid Amino given. are Sequence Reference NCBI and database Prot - Figure 1. Schematic representation of structures of PPIases playing important roles in tumor development and progression. diagrams depicting structures of the of selective cyclophilin, FKBP and purvulin family and metastasis. Sizes of the unprocessed protein are shown in brackets next to the gene name. In the second row, the accessio UniProtKB/Swiss of UniProtKB/Swiss to according designated are amino acid residues of Cyps, FKBPs and Pin1 are indicated. rrm, RNA WD40 repeat. - 128 - Cancer Research Frontiers. 2017; 3(1): 126-143. doi: 10.17980/2017.126 Review Figure 2. Expression profiles of the prototypic members cyclophilin, FKBP and parvulin family across various types of human tumors. Staining profiles for CypA, FKBP12 and Pin1 in human tumor tissues based on immunohistochemisty using tissue micro arrays and archived from The Human Protein Atlas (http://www.proteinatlas.org). Each bar represents data from at least 10 patient samples. close look into the connections between PPIases and involves, but not limited to, muscle differentiation, tumor generation and progression. detoxification of reactive oxygen species