Cytokine & Growth Factor Reviews 32 (2016) 75–84 Contents lists available at ScienceDirect Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr Survey WFIKKN1 and WFIKKN2: “Companion” proteins regulating TGFB activity a, b,c Olivier Monestier *, Véronique Blanquet a INRA, UR1037 Laboratory of Fish Physiology and Genomic, Growth and Flesh Quality Group, Campus de Beaulieu, 35000 Rennes, France b INRA, UMR1061 Unité de Génétique Moléculaire Animale, 87060 Limoges, France c Université de Limoges, 87060 Limoges, France A R T I C L E I N F O A B S T R A C T Article history: Received 10 May 2016 The WFIKKN (WAP, Follistatin/kazal, Immunoglobulin, Kunitz and Netrin domain-containing) protein Received in revised form 7 June 2016 family is composed of two multidomain proteins: WFIKKN1 and WFIKKN2. They were formed by domain Accepted 10 June 2016 shuffling and are likely present in deuterostoms. The WFIKKN (also called GASP) proteins are well known Available online 11 June 2016 for their function in muscle and skeletal tissues, namely, inhibition of certain members of the transforming growth factor beta (TGFB) superfamily such as myostatin (MSTN) and growth and Keywords: differentiation factor 11 (GDF11). However, the role of the WFIKKN proteins in other tissues is still poorly GASP1 understood in spite of evidence suggesting possible action in the inner ear, brain and reproduction. GASP2 Further, several recent studies based on next generation technologies revealed differential expression of WFIKKN WFIKKN1 and WFIKKN2 in various tissues suggesting that their function is not limited to MSTN and GDF11 WFIKKNRP inhibition in musculoskeletal tissue. In this review, we summarize current knowledge about the WFIKKN Myostatin inhibitors proteins and propose that they are “companion” proteins for various growth factors by providing localized and sustained presentation of TGFB proteins to their respective receptors, thus regulating the balance between the activation of Smad and non-Smad pathways by TGFB. ã 2016 Elsevier Ltd. All rights reserved. Contents 1. Introduction . 76 2. Modular domain structure of the WFIKKN1 and WFIKKN2 proteins . 76 3. The origin of WFIKKN1 and WFIKKN2: multidomain proteins constructed by module shuffling . 76 4. Expression pattern and regulation of WFIKKN1 and WFIKKN2 . 78 4.1. WFIKKN expression in musculoskeletal system . 78 4.2. WFIKKN expression in brain . 78 4.3. WFIKKN expression in other tissues or cell lines . 78 5. Role of WFIKKN in MSTN and GDF11 inhibition . 79 6. Evidences for other functions of WFIKKN . 80 6.1. Function of the WFIKKN antiproteasic modules . 80 6.2. WFIKKN proteins interact with several TGFB superfamily proteins . 80 6.3. WFIKKN are expressed in various tissues . 80 6.4. Polymorphisms of WFIKKN1 and WFIKKN2 are linked with ovulation rate and autism . 80 Abbreviations: WFIKKN, WAP, Follistatin/kazal, Immunoglobulin, Kunitz And Netrin Domain Containing protein; TGFB, transforming growth factor beta; MSTN, myostatin; GDF11, growth and differentiation factor 11; GASP, growth and differentiation factor-associated serum protein; WAP, Whey Acidic Protein; NTR domain, netrin domain; KU, kunitz domain; BMP, Bone morphogenetic protein; PCoLCE, type I procollagen C-proteinase enhancer proteins; TIMPs, tissue inhibitors of metalloproteinases; IgC2, immunoglobulin C2 type domain; FSTL, follistatin-like protein; ADAMTSL, a disintegrin-like and metalloprotease domain with thrombospondin type I motifs-like; WGD, whole genome duplication; PPAR, peroxisome proliferator-activated receptor; MAV, meninges and associated vasculature; LAP, latency associated peptide; FST, follistatin; ACVR, activing receptor; ALK, Anaplastic lymphoma kinase; ERK, Extracellular signal-regulated kinases; JNK, c-Jun N-terminal kinases; PI3K, Phosphoinositide 3-kinase. * Corresponding author. E-mail addresses: [email protected] (O. Monestier), [email protected] (V. Blanquet). http://dx.doi.org/10.1016/j.cytogfr.2016.06.003 1359-6101/ã 2016 Elsevier Ltd. All rights reserved. 76 O. Monestier, V. Blanquet / Cytokine & Growth Factor Reviews 32 (2016) 75–84 7. WFIKKN inhibition of TGFB is just partial . 81 8. Conclusion . 82 Acknowledgements . 82 References . 82 1. Introduction (called also four-disulfide core motif). A WAP domain is a functional motif found in many proteins that exhibit serine WFIKKN1 and WFIKKN2 (also called Growth and differentiation protease inhibition activity [24–27]. factor Associated Serum Protein (GASP) 2 and 1, respectively) are – kazal-type serine protease inhibitors and follistatin-like domain. secreted proteins originally discovered in 2000 and 2002 by Composed of ten cysteines, kazal-type inhibitors are the most Trexler et al. [1,2]. Due to their predicted protein domain studied canonical proteinase inhibitors, and the classical kazal composition and their ubiquitous expression, these proteins are domain structure includes a central alpha helix inserted assumed to form a family of multivalent protease inhibitors. In between two beta-strands and a third toward the C terminus 2003, a major advance in the understanding of the function of this [25,26,28,29]. kazal-like domains are also seen in the extracel- gene family was made when WFIKKN2 was described as an MSTN lular part of agrins which are not known to have proteinase associated protein found in human and mouse sera that could inhibitory effect but are implicated in the interaction of agrin specifically inhibit MSTN, but not activin activity [3]. Since 2003, with BMP2, BMP4 and TGFB1 [30]. many studies confirmed that the WFIKKN proteins act as myostatin – two kunitz domains (KU1 and KU2), which are usually present in and GDF11 inhibitors [4–9] and are implicated in muscle growth proteins that belong to the MEROPS inhibitor family I2 or the [10–14]. However, only weak effects on muscle tissue were kunitz/bovine pancreatic trypsin inhibitor family and inhibit observed after overexpression or inactivation of Wfikkn1/Wfikkn2 proteases of the S1 family [25,26,28]. Their size is about 50 in mice [7,9]. Further, several recent studies based on high residues with few secondary structures and their fold is throughput next generation technologies (microarray, RNAseq, . constrained by three disulphide bonds. ) revealed differential expression of WFIKKN1 and WFIKKN2 in – and the NTR module in the C-terminal part of the WFIKKN various tissues and conditions suggesting that their function is not proteins, also found in the C-terminal part of netrins, C3, C4, and limited to MSTN and GDF11 inhibition in muscle and skeletal C5 components of the complement system, secreted frizzled- tissues. Nevertheless, the role of members of this gene family in related proteins, type I procollagen C-proteinase enhancer other tissues is still poorly understood despite evidence suggesting proteins (PCoLCE), as well as in the N-terminal part of tissue possible action in the inner ear [15], brain [16–19] and reproduc- inhibitors of metalloproteinases (TIMPs) [1,25,26,31]. The NTR tion [20,21]. We summarize here current knowledge about module is a basic domain containing six conserved cysteines, WFIKKN1 and WFIKKN2 and propose a more generic function which are likely to form internal disulphide bonds, and several for these two proteins. conserved blocks of hydrophobic residues [31]. Information on the role of the NTR domains in the other NTR domain-containing 2. Modular domain structure of the WFIKKN1 and WFIKKN2 proteins is limited. There have been no reports of proteinase proteins inhibitory activity in the NTR domains of netrins, C3/C4/C5 complement proteins, WFIKKN1 and WFIKKN2. In contrast, this In mammals, the WFIKKN family is composed of two domain is frequently involved in binding to heparin or related paralogous genes of 3–7 kb (Table 1) structured in two exons macromolecules [32–36]. and one intron. The short first exon (570 bp) encodes a signal peptide for secretion and a WAP (Whey Acidic Protein) domain Considering the posttranslational maturation, we know that whereas the last larger exon encodes a follistatin/kazal domain, an WFIKKN2 is a glycoprotein and contain two N-glycans, one located IgC2 (immunoglobulin C2 type) domain, two kunitz domains and a between the IgC2 and the KU1 domains (N314) and the other in the NTR (netrin) domain, hence the name: WAP, Follistatin/kazal, NTR domain (N514). The loss of these N-glycans leads to a decrease Immunoglobulin, Kunitz and NTR domain-containing protein. in protein secretion rate but does not appear to affect the WFIKKN1 and 2 share about 55% identity (Table 2), but the 6 functional activity of the protein in C2C12 cells [37]. Furthermore, modules including 38 cysteines are well conserved in all vertebrate several mucin-type O-glycans seem to be present between the WFIKKN proteins [22]. Five out of six domains of the WFIKKN kazal and the IgC2 domains. proteins exhibit homology-predicted antiprotease activity, so these proteins are classified as heterotypic compound inhibitors 3. The origin of WFIKKN1 and WFIKKN2: multidomain proteins (I90 family of peptidase inhibitors) along with only two other constructed by module shuffling proteins: the Red Sea turtle chelonianin and human eppin [23]. These antiproteasic domains include: WFIKKN1 and WFIKKN2 are paralogous genes as supported by paralogons and blocks of synteny [22,38]. These genes are present – WAP domain composed of a characteristic sequence motif of in all mammals, and one copy of WFIKKN1 and two of WFIKKN2 are eight cysteines found in a four-disulfide core arrangement present in some fish species [4,22]. A unique ancestral gene was Table 1 WFIKKN general information (Ensembl). Chromosome Gene size (kb) Transcrit size (bp) Exons number Protein size (aa) Human WFIKKN1 16 3.19 2018 2 548 Mouse WFIKKN1 17 3.23 2530 2 552 Human WFIKKN2 17 6.94 3588 2 576 Mouse WFIKKN2 11 6.75 3516 2 571 Download English Version: https://daneshyari.com/en/article/5531219 Download Persian Version: https://daneshyari.com/article/5531219 Daneshyari.com.