ROR1, an embryonic protein with an emerging role in cancer biology

Borcherding, Nicholas; Kusner, David; Liu, Guanghui; Zhang, Weizhou

doi:10.1007/s13238-014-0059-7

Cited by 126 publications

(119 citation statements)

References 47 publications

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“…ROR1 [previously known as neurotrophic tyrosine kinase, receptorrelated 1 (NTRKR1)] is an integral transmembrane protein that consists of three extracellular conserved domains (Ig-like, frizzled, and kringle) and four intracellular domains (one tyrosine kinase, two serine/threonine-rich, and one proline-rich) (29). Ror1 mutant mice exhibit a variety of phenotypic defects within skeletal and urogenital systems and display a postnatal growth retardation phenotype (12).…”

Section: Discussionmentioning

confidence: 99%

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Diaz‐Horta

Abad

Sennaroḡlu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicitymatched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.deafness | whole-exome sequencing | inner ear | innervation | NF-κB S ensorineural hearing loss (SNHL) is diagnosed in approximately 1 per 500 newborns (1). A genetic etiology is present in more than half of the cases. Inner ear anomalies (IEAs), demonstrated with computerized tomography or magnetic resonance imaging, are associated with SNHL in about one-third of individuals (2). Although IEAs can be diagnosed in patients with other clinical manifestations, such as those seen in Waardenburg [Mendelian Inheritance in Man (MIM) 193500], Pendred (MIM 274600), or BOR (MIM 113650) syndromes, the majority of cases fall into the category of nonsyndromic deafness. Despite recent progress in identifying genes that determine many forms of hearing loss (hereditaryhearingloss.org/), the genetic basis of IEAs in humans remains largely unknown.The inner ear is a complex organ that is built from a simple structure, referred to as the otocyst, through a series of morphogenetic events. Roughly, it consists of a dorsal vestibular and a ventral auditory component (3). Studies in model organisms have identified a number of genes that play roles in proper development of the inner ear. Mouse models have been particularly relevant because the anatomy and physiology of the murine auditory system are similar to those of humans. Mutations in human orthologs of many of these genes have been reported to cause deafness in humans as well (4).Next-generation sequencing technologies have allowed rapid identification of novel human deafness genes. Appro...

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Section: Discussionmentioning

confidence: 99%

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Diaz‐Horta

Abad

Sennaroḡlu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…As a model antibody, we chose to use variable regions of a murine mAb (2A2) 28 that is specific for the cancer cell-associated surface molecule ROR1. 29,30 L11 cells were transposed using DNA mixes of HC/LC/TP, and were either selected by simultaneous addition of hygromycin and puromycin 24 hours after electroporation and cultured under selective pressure for 5 days, or were subcultured without antibiotic selection for the same amount of time. Cells were then double-stained for antibody surface expression using PE-coupled, Fc-specific anti-human IgG, and for antigen-binding using soluble, strep-tagged ROR1 that was detected using a fluorophore-labeled strep-tag-specific antibody.…”

Section: Transposition-mediated Antibody Surface Display and Secretiomentioning

confidence: 99%

“…30,37,38 Here, we used sets of humanized variable regions designed by grafting of CDRs into framework regions derived from a database of somatically hypermutated human sequences, and generated transposable libraries as described before. The humanized libraries consisted of 64 VH £ 49 VL and 101 VH £ 82 VL for 2A2 and R11, respectively ( Fig.…”

Section: Transpo-mab Screening Of Humanized Anti-ror1 Antibody Librariesmentioning

confidence: 99%

Transpo-mAb display: Transposition-mediated B cell display and functional screening of full-length IgG antibody libraries

Waldmeier

Hellmann

Gutknecht

et al. 2016

mAbs

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In vitro antibody display and screening technologies geared toward the discovery and engineering of clinically applicable antibodies have evolved from screening artificial antibody formats, powered by microbial display technologies, to screening of natural, full-IgG molecules expressed in mammalian cells to readily yield lead antibodies with favorable properties in production and clinical applications. Here, we report the development and characterization of a novel, next-generation mammalian cell-based antibody display and screening platform called Transpo-mAb Display, offering straightforward and efficient generation of cellular libraries by using non-viral transposition technology to obtain stable antibody expression. Because Transpo-mAb Display uses DNA-transposable vectors with substantial cargo capacity, genomic antibody heavy chain expression constructs can be utilized that undergo the natural switch from membrane bound to secreted antibody expression in B cells by way of alternative splicing of Ig-heavy chain transcripts from the same genomic expression cassette. We demonstrate that stably transposed cells co-express transmembrane and secreted antibodies at levels comparable to those provided by dedicated constructs for secreted and membrane-associated IgGs. This unique feature expedites the screening and antibody characterization process by obviating the need for intermediate sequencing and re-cloning of individual antibody clones into separate expression vectors for functional screening purposes. In a series of proof-of-concept experiments, we demonstrate the seamless integration of antibody discovery with functional screening for various antibody properties, including binding affinity and suitability for preparation of antibody-drug conjugates.

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“…ROR1 was shown to be expressed at high levels in several hematological malignancies such as chronic lymphocytic leukemia (CLL), MCL, chronic myelogenous leukemia, t(1;19) B-acute lymphoblastic leukemia (B-ALL), as well as many other solid tumors. 15 ROR1 ligand Wnt5a shares a similar expression pattern in blood malignancies, notably with high levels in B-cell lymphomas compared with no expression on healthy lymphocytes. [16][17][18] Wnt5a binding to ROR1 induces ROR1/ROR2 heterodimerization and subsequent engagement of guanine exchange factor intracellular signaling, resulting in leukemia cell survival and proliferation via activation of Rho GTPases in CLL cells.…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma

et al. 2017

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ROR1, an embryonic protein with an emerging role in cancer biology

Cited by 126 publications

References 47 publications

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Transpo-mAb display: Transposition-mediated B cell display and functional screening of full-length IgG antibody libraries

Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma

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