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Rhbdf2 Mutations Increase Its Protein Stability and Drive EGFR

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Rhbdf2 Mutations Increase Its Protein Stability and Drive EGFR Rhbdf2 mutations increase its protein stability and PNAS PLUS drive EGFR hyperactivation through enhanced secretion of amphiregulin Vishnu Hosur, Kenneth R. Johnson, Lisa M. Burzenski, Timothy M. Stearns, Richard S. Maser, and Leonard D. Shultz1 The Jackson Laboratory, Bar Harbor, ME 04609 Edited by Dennis A. Carson, University of California at San Diego, La Jolla, CA, and approved April 17, 2014 (received for review December 23, 2013) The rhomboid 5 homolog 2 (Rhbdf2) gene encodes an inactive mutations in RHBDF2 (p.I186T, p.P189L, and p.D188N), the rhomboid (iRhom) protease, iRhom2, one of a family of enzymes gene encoding iRhom2, cause tylosis with human esophageal containing a long cytosolic N terminus and a dormant peptidase cancer, which is characterized by palmoplantar and oral hy- domain of unknown function. iRhom2 has been implicated in ep- perkeratosis (10). Other studies have revealed that iRhom1 ithelial regeneration and cancer growth through constitutive acti- promotes the survival of epithelial tumors through EGFR trans- vation of epidermal growth factor receptor (EGFR) signaling. activation (5), whereas somatic mutations in iRhom2 are strongly However, little is known about the physiological substrates for linked to gain of EGFR signaling (11). Although the mechanisms iRhom2 or the molecular mechanisms underlying these functions. underlying the pathogenesis of cancer are evolving, these studies We show that iRhom2 is a short-lived protein whose stability can further strengthen the link between iRhoms and EGFR signaling. be increased by select mutations in the N-terminal domain. In turn, Rhomboids have been extensively characterized in Drosophila, these stable variants function to augment the secretion of EGF in which changes in EGFR signaling can be detected by studying family ligands, including amphiregulin, independent of metallo- the wing phenotype (12, 13), whereas in mice, such alterations protease a disintegrin and metalloproteinase 17 (ADAM17) activity. can be analyzed by examining hair follicle development (14), In vivo, N-terminal iRhom2 mutations induce accelerated wound response to wound healing (15), and tumorigenesis (16). Here, GENETICS healing as well as accelerated tumorigenesis, but they do not drive we show that a spontaneous deletion within the rhomboid 5 spontaneous tumor development. This work underscores the phys- homolog 2 (Rhbdf2) gene in mice underlies the curly-bare (cub) iological prominence of iRhom2 in controlling EGFR signaling events mutation, in which loss of the cytosolic N-terminal domain of involved in wound healing and neoplastic growth, and yields in- iRhom2 causes subsequent effects on hair follicle development, sight into the function of key iRhom2 domains. wound healing, and tumorigenesis. We find that iRhom2 is a short-lived protein but that gain-of-function mutations in the curly bare | ERAD | tylosis | epithelial cancer | pseudoenzyme N terminus (tylosis) or loss of the N terminus (cub mutation) increase mutant protein stability, leading to metalloprotease- nactive rhomboids (iRhoms) are highly conserved but pro- independent secretion of the EGFR ligand amphiregulin (AREG). Iteolytically inactive intramembrane proteins (1). iRhoms are Using a genetic modifier of the cub phenotype (Mcub), we characterized by a long cytosolic N-terminal domain, a conserved demonstrate that AREG is a physiological target of iRhom2. We cysteine-rich iRhom homology domain (IRHD), and a dormant also identify key amino acids in the peptidase domain of iRhom2 proteolytic site lacking an active-site serine residue within the that are necessary for AREG secretion, suggesting that the peptidase domain (1). Recently, Greenblatt et al. (2) reported peptidase domain of this pseudoenzyme might be functional de- that Derlin-1 belongs to the rhomboid family and suggested that a dual role exists for the cytosolic and peptidase domains of this Significance novel rhomboid pseudoprotease. They showed that although the cytosolic domain of Derlin-1 is essential in mammalian cells for Epidermal growth factor receptor (EGFR) signal transduction clearance of misfolded proteins from the endoplasmic reticulum, plays a major role in growth, proliferation, and differentiation the transmembrane domain is required to interact with its substrates of mammalian cells. Although inactive rhomboids (iRhoms) are (2), suggesting that these two domains have distinctive functions. cardinal regulators of EGFR signaling in Drosophila mela- The physiological significance of these domains is unclear. nogaster, their physiological role in regulating EGFR signal- Despite their lack of proteolytic activity, iRhoms participate in a ing and their substrates in mammals remain unclear. Here, diverse range of functions in a variety of species, including regulation we show that iRhoms are short-lived proteins, but dominant of epidermal growth factor receptor (EGFR) signaling in Drosophila mutations increase their protein stability and stimulate secre- melanogaster (3), survival of human squamous epithelial cancer cells tion of specific EGF family ligand amphiregulin independent of (4, 5), misfolded protein clearance from endoplasmic reticulum metalloprotease activity. This study demonstrates the signifi- membranes in mammalian cell lines (2), induction of migration in cance of mammalian iRhoms in regulating an EGFR signaling α primary mouse keratinocytes (6), secretion of soluble TNF- in mice event that promotes accelerated wound healing and triggers (7, 8), and regulation of substrate selectivity of stimulated a dis- tumorigenesis. Given their ability to regulate EGFR signaling in integrin and metalloproteinase 17 (ADAM17)-mediated metal- parallel with metalloproteases, iRhoms can be potential ther- loprotease shedding in mouse embryonic fibroblasts (MEFs) (6, 9). apeutic targets in impaired wound healing and cancer. Although the physiological targets of iRhoms are largely unknown, mounting literature suggests that EGF-like ligands are potential Author contributions: V.H., R.S.M., and L.D.S. designed research; V.H., K.R.J., and L.M.B. substrates. For example, studies in D. melanogaster and in mam- performed research; V.H. contributed new reagents/analytic tools; V.H., K.R.J., T.M.S., R.S.M., malian cell lines showed that iRhoms could negatively regulate and L.D.S. analyzed data; and V.H. and L.D.S. wrote the paper. EGFR signaling by breaking down EGF-like substrates through The authors declare no conflict of interest. endoplasmic reticulum-associated degradation (ERAD) (3). This article is a PNAS Direct Submission. Recent data also point to a role for iRhoms in EGFR-mediated 1To whom correspondence should be addressed. E-mail: [email protected]. human neoplastic growth. siRNA-mediated silencing of iRhom1 This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. inhibits tumor growth by inducing apoptosis (4). Likewise, missense 1073/pnas.1323908111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1323908111 PNAS Early Edition | 1of10 Downloaded by guest on September 25, 2021 spite lacking a serine residue in the putative active site. This study ABC+/+ cub/cub +/+ mcub/mcub +/+ mcub/mcub mcub/mcub mcub/mcub therefore yields insight into the function of key iRhom domains cub/cub mcub/mcub cub/cub mcub/mcub and establishes a framework for understanding the relationship 500 100 p-Akt Akt between iRhoms, EGFR signaling, and the biological processes 400 p-S6 75 S6 involved in wound healing and tumorigenesis. 300 p-mTOR 50 mTOR Results 200 p-p38 25 p38 100 Percent closure cub Mutation Leads to Hyperactivation of the EGFR Signaling Pathway. p-Egfr 0 0 We previously described a recessive mouse mutation named Relative fluorescence units Egfr 01234503691215 cub, which is characterized by a hairless phenotype (17). We pre- Number of MEFs (x10000) Time (h) actin viously mapped the cub mutation to a locus on distal chromosome D Day 0 Day 7 Day 14 Day 21 Day 28 (Chr) 11 and mapped a dominant Mcub to a 10-cM interval on Chr 5 (17). A single copy of the dominant Mcub allele in combination +/+ with the cub/cub genotype results in a full, wavy coat rather than the hairless coat of cub/cub mcub/mcub mice (17). Because of the mcub/mcub potential relationship between the hair coat phenotypes and EGFR signaling (18, 19), we investigated whether the cub/cub mcub/mcub cub/cub genotype might also be associated with other aspects of altered mcub/mcub EGFR signaling, such as cell proliferation and cell migration. E +/+ mcub/mcub F 120 cub/cub mcub/mcub We performed proliferation, cell migration (scratch-wound 0 Days 7 Days 14 Days healing), and immunoblot assays on mouse MEFs isolated from 100 + + / 80 +/+ M cub/cub mcub/mcub and control ( mcub/mcub)mice.Thecub/cub E 60 mcub/mcub MEFs had significantly higher rates of proliferation mcub/mcub 40 and migration relative to control MEFs (Fig. 1 A and B). These 20 M E changes were associated with significant increases in the phos- % Hole remaining 0 cub/cub 0 7 14 21 28 phorylation of canonical signal transduction proteins of the EGFR Days mcub/mcub pathway, including, Akt, S6, mTOR, and p38 (Fig. 1C). Further, we observed a significant reduction in cell-surface EGFR levels Fig. 1. cub mutation accelerates EGFR-related cell proliferation and mi- in cub/cub mcub/mcub MEFs (Fig. 1C), indicating internalization gration, as well as cutaneous healing. (A) Quantitation of MEFs using and constitutive activation of EGFR signaling (20–22). a proliferation assay (SI Materials and Methods).
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