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Uzma Malik, Aneela Javed
The human leucine-rich repeats and immunoglobulin like domains (LRIG) are evolutionary conserved family of single-pass transmembrane proteins. LRIG gene family includes three members, LRIG1 (formerly LIG1), LRIG2 and LRIG3, all of which are differentially expressed in human tissues and have long been proposed to be tumor suppressors. However, recently accumulated evidence on LRIG protein expression in human cancer appears to be inconsistent with this belief, as LRIG proteins have been found to be upregulated in certain tumors...
September 7, 2016: Current Cancer Drug Targets
Susan van Erp, Dianne M A van den Heuvel, Yuki Fujita, Ross A Robinson, Anita J C G M Hellemons, Youri Adolfs, Eljo Y Van Battum, Anna M Blokhuis, Marijn Kuijpers, Jeroen A A Demmers, Håkan Hedman, Casper C Hoogenraad, Christian Siebold, Toshihide Yamashita, R Jeroen Pasterkamp
Many guidance receptors are proteolytically cleaved by membrane-associated metalloproteases of the ADAM family, leading to the shedding of their ectodomains. Ectodomain shedding is crucial for receptor signaling and function, but how this process is controlled in neurons remains poorly understood. Here, we show that the transmembrane protein Lrig2 negatively regulates ADAM-mediated guidance receptor proteolysis in neurons. Lrig2 binds Neogenin, a receptor for repulsive guidance molecules (RGMs), and prevents premature Neogenin shedding by ADAM17 (TACE)...
December 7, 2015: Developmental Cell
Burcu Bulum, Z Birsin Özçakar, Duygu Duman, Filiz Başak Cengiz, Aslı Kavaz, Berk Burgu, Esra Baskın, Nilgün Çakar, Tarkan Soygür, Mesiha Ekim, Mustafa Tekin, Fatoş Yalçınkaya
BACKGROUND: Urofacial syndrome (UFS) is characterised by congenital bladder dysfunction accompanied by a characteristic abnormal grimace upon smiling and crying. In recent years, biallelic mutations of HPSE2 and LRIG2 have been reported in UFS patients. Non-neurogenic neurogenic bladder (NNNB) has a bladder identical to UFS without typical facial features. The aim of this study was to analyse HPSE2 mutations in patients with UFS and NNNB or severe lower urinary tract dysfunction (LUTD) without abnormal facial expression...
2015: Nephron
Samuel Kvarnbrink, Terese Karlsson, Karolina Edlund, Johan Botling, David Lindquist, Karin Jirström, Patrick Micke, Roger Henriksson, Mikael Johansson, Håkan Hedman
BACKGROUND: The leucine-rich repeats and immunoglobulin-like domains (LRIG) family of transmembrane proteins are involved in the regulation of cellular signal transduction. LRIG1 is an endogenous inhibitor of receptor tyrosine kinases (RTKs) and an emerging tumor suppressor. In the lung epithelium, the expression of LRIG1 is downregulated by tobacco smoking, and further downregulated in lung squamous cell carcinoma. MATERIAL AND METHODS: The expression of LRIG proteins were analyzed in 347 cases of non-small cell lung cancer (NSCLC) by immunohistochemistry, and LRIG1 mRNA expression was evaluated in 807 lung cancer samples in silico in the Oncomine database...
2015: Acta Oncologica
Qungen Xiao, Yihu Tan, Yang Guo, Hongkuan Yang, Feng Mao, Ruifan Xie, Baofeng Wang, Ting Lei, Dongsheng Guo
The human leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family contains LRIG1, 2 and 3, encoding integral membrane proteins with an ectodomain, a transmembrane domain and a cytoplasmic tail. LRIG1 negatively regulates multiple receptor tyrosine kinases signaling including the epidermal growth factor receptor (EGFR) and is a proposed tumor suppressor. The soluble LRIG1 ectodomain is demonstrated to be shed naturally and inhibit the progression of glioma. However, little is known regarding the functions of LRIG2...
2014: PloS One
Catalina Simion, Maria Elvira Cedano-Prieto, Colleen Sweeney
The leucine-rich repeats and immunoglobulin-like domains (LRIG) family of transmembrane proteins contains three vertebrate members (LRIG1, LRIG2 and LRIG3) and one member each in flies (Lambik) and worms (Sma-10). LRIGs have stepped into the spotlight as essential regulators of growth factor receptors, including receptor tyrosine and serine/threonine kinases. LRIGs have been found to both negatively (LRIG1 and LRIG3) and positively (Sma-10 and LRIG3) regulate growth factor receptor expression and signaling, although the precise molecular mechanisms by which LRIGs function are not yet understood...
2014: Endocrine-related Cancer
David Lindquist, Samuel Kvarnbrink, Roger Henriksson, Håkan Hedman
BACKGROUND: Optimal treatment decisions for cancer patients require reliable prognostic and predictive information. However, this information is inadequate in many cases. Several recent studies suggest that the leucine-rich repeats and immunoglobulin-like domains (LRIG) genes, transcripts, and proteins have prognostic implications in various cancer types. MATERIAL AND METHODS: Relevant literature was identified on PubMed using the key words lrig1, lrig2, and lrig3...
September 2014: Acta Oncologica
Helen M Stuart, Neil A Roberts, Emma N Hilton, Edward A McKenzie, Sarah B Daly, Kristen D Hadfield, Jeffery S Rahal, Natalie J Gardiner, Simon W Tanley, Malcolm A Lewis, Emily Sites, Brad Angle, Cláudia Alves, Teresa Lourenço, Márcia Rodrigues, Angelina Calado, Marta Amado, Nancy Guerreiro, Inês Serras, Christian Beetz, Rita-Eva Varga, Mesrur Selcuk Silay, John M Darlow, Mark G Dobson, David E Barton, Manuela Hunziker, Prem Puri, Sally A Feather, Judith A Goodship, Timothy H J Goodship, Heather J Lambert, Heather J Cordell, Anand Saggar, Maria Kinali, Christian Lorenz, Kristina Moeller, Franz Schaefer, Aysun K Bayazit, Stefanie Weber, William G Newman, Adrian S Woolf
Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant...
April 2015: Journal of the American Society of Nephrology: JASN
Guangchuan Wang, Jie Wu, Huijuan Song
The human leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2) protein has been shown to be of prognostic value in several types of human cancer, however, the expression profiles of LRIG2 have not been described in non-small cell lung cancer (NSCLC). The present study evaluated the mRNA expression of LRIG2 in tumor specimens obtained from 39 NSCLC patients by SYBR Green quantitative polymerase chain reaction and the protein expression of LRIG2 in formalin-fixed paraffin sections obtained from 116 NSCLC patients by immunohistochemistry...
August 2014: Oncology Letters
A K Lindström, D Hellberg
The novel biomarker LRIG3 is a member of the LRIG family (LRIG1-3). While LRIG1 has been associated with favorable prognosis and LRIG2 with poor prognosis in invasive cervical cancer, little is known about the role of LRIG3. The aim of this study was to investigate the expression of LRIG3 in invasive cancer and cervical intraepithelial neoplasia (CIN) for possible correlation with other tumor markers, to hormones and smoking, as a diagnostic adjunct in CIN, and prognostic value in invasive cancer. Cervical biopsies from 129 patients with invasive squamous cell carcinoma and 170 biopsies showing low grade and high grade CIN, or normal epithelium were stained for LRIG3 and 17 additional tumor markers...
2014: European Journal of Histochemistry: EJH
Yaqin Tu, Ping Yang, Jia Yang, Yuchen Xu, Fei Xiong, Qilin Yu, Weikuan Gu, Dinel Pond, Nancy Mendelsohn, Guus A M A Lachmeijer, Shu Zhang, Cong-Yi Wang
The Urofacial (Ochoa) Syndrome (UFS) is a rare autosomal recessive disorder and over 100 patients have been reported thus far. UFS is characterized by the abnormal facial expression and dysfunctional voiding. The patients show a peculiar distortion of the facial expression (grimacing as if in pain or sadness when they tried to smile or laugh) along with urinary tract infection, enuresis, vesicoureteral reflux and hydronephrosis without any underlying neurological lesion and previous urinary obstruction. Some patients are also noted with nocturnal lagophthalmos...
2014: International Journal of Clinical and Experimental Pathology
D Lindquist, A Näsman, M Tarján, R Henriksson, T Tot, T Dalianis, H Hedman
BACKGROUND: The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer has increased rapidly during the past decades. HPV is typically associated with a favourable outcome; however, a need exists for new and more effective prognostic and predictive markers for this disease. Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a tumour suppressor protein that belongs to the LRIG family. LRIG1 expression has prognostic significance in various human cancers, including cervical cancer, where HPV is a key aetiological agent...
April 2, 2014: British Journal of Cancer
Dan Hellberg, Tibor Tot
BACKGROUND/AIM: Histopathological and clinical scores to predict prognosis in cervical cancer have been of limited value. In the present study a tumor marker expression score was evaluated for prognostication in early-stage cervical cancer. MATERIALS AND METHODS: The entire study population included 128 women with invasive squamous cell cervical cancer followed-up for at least 10 years. RESULTS: Expression of 12 tumor markers (epidermal growth factor receptor (EGFR), Ki-67, c-MYC, p53, p27, E-cadherin, CD44, vascular endothelial growth factor receptor (VEGF), cyclooxygenase-2 (COX2), CD4, and leucine-rich immunoglobulin-like repeats-1 (LRIG1) and LRIG2, considered relevant for cervical cancer prognostication was evaluated by immunohistochemistry...
February 2014: Anticancer Research
Tony Del Rio, Allison M Nishitani, Wei-Ming Yu, Lisa V Goodrich
Lrig proteins are conserved transmembrane proteins that modulate a variety of signaling pathways from worm to humans. In mammals, there are three family members - Lrig1, Lrig2, and Lrig3--that are defined by closely related extracellular domains with a similar arrangement of leucine rich repeats and immunoglobulin domains. However, the intracellular domains show little homology. Lrig1 inhibits EGF signaling through internalization and degradation of ErbB receptors. Although Lrig3 can also bind ErbB receptors in vitro, it is unclear whether Lrig2 and Lrig3 exhibit similar functions to Lrig1...
2013: PLoS Genetics
Veronica Rondahl, Camilla Holmlund, Terese Karlsson, Baofeng Wang, Mahmood Faraz, Roger Henriksson, Håkan Hedman
BACKGROUND: The leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins constitute an integral membrane protein family that has three members: LRIG1, LRIG2, and LRIG3. LRIG1 negatively regulates growth factor signaling, but little is known regarding the functions of LRIG2 and LRIG3. In oligodendroglial brain tumors, high expression of LRIG2 correlates with poor patient survival. Lrig1 and Lrig3 knockout mice are viable, but there have been no reports on Lrig2-deficient mice to date...
2013: PloS One
Adrian S Woolf, Helen M Stuart, Neil A Roberts, Edward A McKenzie, Emma N Hilton, William G Newman
The urofacial, or Ochoa, syndrome is characterised by congenital urinary bladder dysfunction together with an abnormal grimace upon smiling, laughing and crying. It can present as fetal megacystis. Postnatal features include urinary incontinence and incomplete bladder emptying due to simultaneous detrusor muscle and bladder outlet contractions. Vesicoureteric reflux is often present, and the condition can be complicated by urosepsis and end-stage renal disease. The syndrome has long been postulated to have neural basis, and it can be familial when it is inherited in an autosomal recessive manner...
April 2014: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Hanine Rafidi, Francisco Mercado, Michael Astudillo, William H D Fry, Matthew Saldana, Kermit L Carraway, Colleen Sweeney
Lrig1 is the founding member of the Lrig family of transmembrane leucine-rich repeat proteins, which also includes Lrig2 and Lrig3. Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including ErbB and Met receptors, and promotes receptor degradation. Lrig1 has recently emerged as both a tumor suppressor and a key regulator of epidermal and epithelial stem cell quiescence. Despite this, little is known of the mechanisms by which Lrig1 is regulated. Lrig3 was recently reported to increase ErbB receptor expression suggesting that it may function in a manner opposite to Lrig1...
July 26, 2013: Journal of Biological Chemistry
Adrian S Woolf, Helen M Stuart, William G Newman
Lower urinary tract and/or kidney malformations are collectively the most common cause of end-stage renal disease in children, and they are also likely to account for a major subset of young adults requiring renal replacement therapy. Advances have been made regarding the discovery of the genetic causes of human kidney malformations. Indeed, testing for mutations of key nephrogenesis genes is now feasible for patients seen in nephrology clinics. Unfortunately, less is known about defined genetic bases of human lower urinary tract anomalies...
March 2014: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Y Wang, E J Poulin, R J Coffey
In baseball parlance, a triple threat is a person who can run, hit and throw with aplomb. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a cell surface protein that antagonises ERBB receptor signalling by downregulating receptor levels. Over 10 years ago, Hedman et al postulated that LRIG1 might be a tumour suppressor. Recently, Powell et al provided in vivo evidence substantiating that claim by demonstrating that Lrig1 loss in mice leads to spontaneously arising, highly penetrant intestinal adenomas...
May 14, 2013: British Journal of Cancer
Helen M Stuart, Neil A Roberts, Berk Burgu, Sarah B Daly, Jill E Urquhart, Sanjeev Bhaskar, Jonathan E Dickerson, Murat Mermerkaya, Mesrur Selcuk Silay, Malcolm A Lewis, M Beatriz Orive Olondriz, Blanca Gener, Christian Beetz, Rita E Varga, Omer Gülpınar, Evren Süer, Tarkan Soygür, Zeynep B Ozçakar, Fatoş Yalçınkaya, Aslı Kavaz, Burcu Bulum, Adnan Gücük, Wyatt W Yue, Firat Erdogan, Andrew Berry, Neil A Hanley, Edward A McKenzie, Emma N Hilton, Adrian S Woolf, William G Newman
Urofacial syndrome (UFS) (or Ochoa syndrome) is an autosomal-recessive disease characterized by congenital urinary bladder dysfunction, associated with a significant risk of kidney failure, and an abnormal facial expression upon smiling, laughing, and crying. We report that a subset of UFS-affected individuals have biallelic mutations in LRIG2, encoding leucine-rich repeats and immunoglobulin-like domains 2, a protein implicated in neural cell signaling and tumorigenesis. Importantly, we have demonstrated that rare variants in LRIG2 might be relevant to nonsyndromic bladder disease...
February 7, 2013: American Journal of Human Genetics
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