Neuronal leucine-rich repeat 1 negatively regulates anaplastic lymphoma kinase in neuroblastoma.
In neuroblastoma (NB), one of the most common paediatric solid tumours, activation of anaplastic lymphoma kinase (ALK) is often associated with poor outcomes. Although genetic studies have identified copy number alteration and nonsynonymous mutations of ALK, the regulatory mechanism of ALK signalling at protein levels is largely elusive. Neuronal leucine-rich repeat 1 (NLRR1) is a type 1 transmembrane protein that is highly expressed in unfavourable NB and potentially influences receptor tyrosine kinase signalling. Here, we showed that NLRR1 and ALK exhibited a mutually exclusive expression pattern in primary NB tissues by immunohistochemistry. Moreover, dorsal root ganglia of Nlrr1+/+ and Nlrr1-/- mice displayed the opposite expression patterns of Nlrr1 and Alk. Of interest, NLRR1 physically interacted with ALK in vitro through its extracellular region. Notably, the NLRR1 ectodomain impaired ALK phosphorylation and proliferation of ALK-mutated NB cells. A newly identified cleavage of the NLRR1 ectodomain also supported NLRR1-mediated ALK signal regulation in trans. Thus, we conclude that NLRR1 appears to be an extracellular negative regulator of ALK signalling in NB and neuronal development. Our findings may be beneficial to comprehend NB heterogeneity and to develop a novel therapy against unfavourable NB.
Children's Cancer Research Center, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.|Department of Molecular Biology and Oncology, Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba 260-8670, Japan.
Shunpei
S
Satoh
Children's Cancer Research Center, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
Atsushi
A
Takatori
Children's Cancer Research Center, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.|Department of Molecular Biology and Oncology, Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba 260-8670, Japan.
Atsushi
A
Ogura
Department of Anatomic Pathology, Graduate School Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan, Chiba 260-8670, Japan.
Kenichi
K
Kohashi
Department of Pediatric Surgery, Graduate School Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Ryota
R
Souzaki
Department of Pediatric Surgery, Graduate School Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Yoshiaki
Y
Kinoshita
Department of Pediatric Surgery, Graduate School Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Tomoaki
T
Taguchi
Children's Cancer Research Center, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
Md Shamim
MS
Hossain
Division of Cancer Genomics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
Miki
M
Ohira
Division of Biochemistry &Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
Yohko
Y
Nakamura
Children's Cancer Research Center, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.|Department of Molecular Biology and Oncology, Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba 260-8670, Japan.|Division of Biochemistry &Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.|Saga Medical Centre KOSEIKAN, 400 Nakabaru, Kase-machi, Saga 840-8571, Japan.
Akira
A
Nakagawara
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005110:Extracellular Space / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
C494421:LRRN1 protein, human; C099580:Lrrn1 protein, mouse; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases