Lrig2-Deficient Mice Are Protected against PDGFB-Induced Glioma

Rondahl, Veronica; Holmlund, Camilla; Karlsson, Terese; Wang, Baofeng; Faraz, Mahmood; Henriksson, Roger; Hedman, Håkan

doi:10.1371/journal.pone.0073635

Cited by 37 publications

(63 citation statements)

References 40 publications

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“…13 Thus, the HPSE2 gene product may modify heparanase 1 activity within ganglia. Our observation that LRIG2 was also present in pelvic ganglia, combined with a report that LRIG2 modifies growth factor signaling in glioma cells, 24 suggests that LRIG2 may operate in similar biologic pathways as heparanase 2. If autonomic nerve function is perturbed, then the cyclic low-pressure storage of urine and complete bladder emptying will be impaired.…”

supporting

confidence: 74%

Urinary Tract Effects of HPSE2 Mutations

Stuart

Roberts

Hilton

et al. 2015

Journal of the American Society of Nephrology

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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 nonneurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS.

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supporting

confidence: 74%

Urinary Tract Effects of HPSE2 Mutations

Stuart

Roberts

Hilton

et al. 2015

Journal of the American Society of Nephrology

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“…The antibodies were obtained from various sources as follows: anti-phosphotyrosine (p-Tyr) and anti-phospho-TrkB (p-Tyr 705) were from Santa Cruz Biotechnology, anti-TrkB was from BD Biosciences Pharmingen, rabbit polyclonal anti-Lrig1 extracellular domain (gift from Dr. Satoshi Itami, University of Osaka, Osaka, Japan) [19,24], anti-Lrig1 intracellular domain was from R&D Systems, anti-HA was from Roche, rabbit polyclonal anti-Lrig2-147 [58] and rabbit polyclonal anti-Lrig3-207 were from Dr. Håkan Hedman laboratory (Umeå University, Sweden), antiphospho-MAPK (Thr-202/Tyr-204) was from New England Biolabs, anti-bIII-tubulin was from Promega, anti-MAP-2, antiS100b, and anti-Flag (M2) were from Sigma, and anti-ubiquitin was from Millipore.…”

Section: Antibodiesmentioning

confidence: 99%

Lrig1 is a cell‐intrinsic modulator of hippocampal dendrite complexity and BDNF signaling

et al. 2016

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Even though many extracellular factors have been identified as promoters of general dendritic growth and branching, little is known about the cell-intrinsic modulators that allow neurons to sculpt distinctive patterns of dendrite arborization. Here, we identify Lrig1, a nervous system-enriched LRR protein, as a key physiological regulator of dendrite complexity of hippocampal pyramidal neurons. Lrig1-deficient mice display morphological changes in proximal dendrite arborization and defects in social interaction. Specifically, knockdown of Lrig1 enhances both primary dendrite formation and proximal dendritic branching of hippocampal neurons, two phenotypes that resemble the effect of BDNF on these neurons. In addition, we show that Lrig1 physically interacts with TrkB and attenuates BDNF signaling. Gain and loss of function assays indicate that Lrig1 restricts BDNF-induced dendrite morphology. Together, our findings reveal a novel and essential role of Lrig1 in regulating morphogenic events that shape the hippocampal circuits and establish that the assembly of TrkB with Lrig1 represents a key mechanism for understanding how specific neuronal populations expand the repertoire of responses to BDNF during brain development.

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“…Less is known regarding the specific molecular functions of LRIG2 and LRIG3 although they do not appear to have the same global ability to decrease growth factor receptor expression. LRIG2 has no significant effect on the expression of EGFR, ErbB2 (Rafidi et al , 2013) or PDGFRα/β (Rondahl et al , 2013) while LRIG3 has been found to oppose LRIG1 (Rafidi et al , 2013) and increase expression of ErbBs 1-4 (Rafidi et al , 2013). LRIG1 limits LRIG3 action by promoting its proteolytic degradation, highlighting a complex cross-talk amongst LRIG family members (Rafidi et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

“…LRIG1 has been identified as a negative regulator of several receptor tyrosine kinases including ErbBs 1-4 (Laederich et al , 2004, Gur et al , 2004), EGFRvIII (Stutz et al , 2008), Met (Shattuck et al , 2007), Ret (Ledda et al , 2008) and PDGFR-α (Rondahl et al , 2013). With the exception of the Ret receptor and the PDGFR-α (for which it was not examined), LRIG1 has been found to increase the ubiquitination and decrease the half –life of its targets.…”

Section: Introductionmentioning

confidence: 99%

The LRIG family: enigmatic regulators of growth factor receptor signaling

Simion¹,

Cedano-Prieto²,

Sweeney³

2014

Endocrine-Related Cancer

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The LRIG (leucine-rich repeats and immunoglobulin-like domains) family of transmembrane proteins contains three vertebrate members (LRIG1, LRIG2, 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, LRIG3) and positively (Sma-10, LRIG3) regulate growth factor receptor expression and signaling, although the precise molecular mechanisms by which LRIGs function are not yet understood. The most is known about LRIG1, which was recently demonstrated to be a tumor suppressor. Indeed, in vivo experiments reinforce the essential link between LRIG1 and repression of its targets for tissue homeostasis. LRIG1 has also been identified as a stem cell marker and regulator of stem cell quiescence in a variety of tissues, discussed within. Comparably less is known about LRIG2 and LRIG3 although studies to date suggest that their functions are largely distinct from LRIG1 and that they likely do not serve as growth/tumor suppressors. Finally, the translational applications of expressing soluble forms of LRIG1 in LRIG1-deficient tumors are being explored and hold tremendous promise.

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Lrig2-Deficient Mice Are Protected against PDGFB-Induced Glioma

Cited by 37 publications

References 40 publications

Urinary Tract Effects of HPSE2 Mutations

Urinary Tract Effects of HPSE2 Mutations

Lrig1 is a cell‐intrinsic modulator of hippocampal dendrite complexity and BDNF signaling

The LRIG family: enigmatic regulators of growth factor receptor signaling

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