Characterization of the expression of the ALK receptor tyrosine kinase in mice

Vernersson, Emma; Khoo, Nelson K.S.; Henriksson, Maria L.; Roos, Göran; Palmer, Ruth; Hållberg, Bengt

doi:10.1016/j.modgep.2005.11.006

Cited by 152 publications

(134 citation statements)

References 15 publications

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“…23,24 Since ALK expression is maintained, albeit at a lower level, in the adult brain, it might play an important role both in the normal development and function of the nervous system. Interestingly, two recent papers analyzed the temporal spatial expression of the ALK receptor during the development of mice 30 and Figure 1. Model for ALK positive and negative signaling.…”

Section: Alk Is Involved In Developmentmentioning

confidence: 99%

ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer

Allouche¹

2007

Cell Cycle

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Section: Alk Is Involved In Developmentmentioning

confidence: 99%

ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer

Allouche¹

2007

Cell Cycle

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“…Although many studies have addressed the mechanisms of action used by oncogenic ALK fusion proteins (primarily NPM-ALK), the physiological functions of ALK and its downstream targets in mouse and humans are far from clear. In mammals, ALK has been suggested to be involved in the normal development and function of the nervous system (Iwahara et al, 1997;Morris et al, 1997;Vernersson et al, 2006;Bilsland et al, 2008). However, the reported presence of differently sized ALK mRNA, suggests that differential splicing and additional functions of ALK may exist (Morris et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Anaplastic lymphoma kinase activates the small GTPase Rap1 via the Rap1-specific GEF C3G in both neuroblastoma and PC12 cells

et al. 2010

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Many different types of cancer originate from aberrant signaling from the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK), arising through different translocation events and overexpression. Further, activating point mutations in the ALK domain have been recently reported in neuroblastoma. To characterize signaling in the context of the full-length receptor, we have examined whether ALK is able to activate Rap1 and contribute to differentiation/proliferation processes. We show that ALK activates Rap1 via the Rap1-specific guaninenucleotide exchange factor C3G, which binds in a constitutive complex with CrkL to activated ALK. The activation of the C3G/Rap1 pathway results in neurite outgrowth of PC12 cells, which is inhibited by either overexpression of Rap1GAP or siRNA-mediated knockdown of Rap1 itself or the guanine nucleotide exchange factor C3G. Significantly, this pathway also appears to function in the regulation of proliferation of neuroblastoma cells such as SK-N-SH and SH-SY5Y, because abrogation of Rap1 activity by Rap1-specific siRNA or overexpression of Rap1GAP reduces cellular growth. These results suggest that ALK activation of Rap1 may contribute to cell proliferation and oncogenesis of neuroblastoma driven by gain-of-function mutant ALK receptors.

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“…However, they are thought to play a role in the development of the mammalian nervous system. mRNA analysis from different mouse tissues has revealed that ALK mRNA is dominantly expressed in brain and spinal cord during mouse embryogenesis and diminishes after birth (16,17). ALK −/− mice are viable and fertile, with some alterations in behavioral tests (18).…”

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confidence: 99%

Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand–receptor interactions

Reshetnyak

Murray

Shi

et al. 2015

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

137

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Receptor tyrosine kinases (RTKs) are a class of cell surface receptors that, upon ligand binding, stimulate a variety of critical cellular functions. The orphan receptor anaplastic lymphoma kinase (ALK) is one of very few RTKs that remain without a firmly established protein ligand. Here we present a novel cytokine, FAM150B, which we propose naming augmentor-α (AUG-α), as a ligand for ALK. AUG-α binds ALK with high affinity and activates ALK in cells with subnanomolar potency. Detailed binding experiments using cells expressing ALK or the related receptor leukocyte tyrosine kinase (LTK) demonstrate that AUG-α binds and robustly activates both ALK and LTK. We show that the previously established LTK ligand FAM150A (AUG-β) is specific for LTK and only weakly binds to ALK. Furthermore, expression of AUG-α stimulates transformation of NIH/3T3 cells expressing ALK, induces IL-3 independent growth of Ba/F3 cells expressing ALK, and is expressed in neuroblastoma, a cancer partly driven by ALK. These experiments reveal the hierarchy and specificity of two cytokines as ligands for ALK and LTK and set the stage for elucidating their roles in development and disease states.cell signaling | surface receptors | phosphorylation | cancer | protein kinases R eceptor tyrosine kinases (RTKs) are cell surface receptors that serve as a signaling relay across the membrane for growth factors, cytokines, and hormones. They function to coordinate proliferation, differentiation, cell survival, and metabolism in multicellular organisms. The era of RTK study began more than half of a century ago (reviewed in ref. 1) and has significantly advanced over the last 3 decades, with numerous studies shedding light on the function, structure, and regulation of RTKs and their ligands (2-4).The RTK anaplastic lymphoma kinase (ALK) was originally identified in anaplastic large-cell non-Hodgkin's lymphoma as an oncogenic fusion protein with nucleophosmin resulting from a 2;5 chromosomal translocation (5, 6). The ALK gene is a hotspot for a variety of chromosomal translocations that result in the formation of fusion proteins that undergo spontaneous dimerization, leading to constitutive activation of the ALK kinase domain (reviewed in refs. 7 and 8). These chimeric ALK proteins were shown to drive numerous human cancers, both in hematopoietic malignancies and in solid tumors (7). Full-length, nonchimeric ALK is a driving force in neuroblastoma (NBL), where genetic studies have identified it as a major target of genetic alterations (i.e., gene amplification and somatic and germline mutations) (7,(9)(10)(11)(12). The majority of missense mutations in ALK found in NBL are located in the kinase domain and lead to constitutive receptor activation. Amplification of ALK and coamplification with the N-myc proto-oncogene (MYCN) (both genes are located on chromosome 2p) drive and cooperate in NBL progression (13). Collectively, these studies underscore the role of ALK in tumorigenesis, along with approval by the US Food and Drug Administration of an ALK inhibit...

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Characterization of the expression of the ALK receptor tyrosine kinase in mice

Cited by 152 publications

References 15 publications

ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer

ALK is a Novel Dependence Receptor: Potential Implications in Development and Cancer

Anaplastic lymphoma kinase activates the small GTPase Rap1 via the Rap1-specific GEF C3G in both neuroblastoma and PC12 cells

Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand–receptor interactions

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