A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in <i>Drosophila melanogaster</i>

Lorén, Christina E.; Englund, Camilla; Grabbe, Caroline; Hållberg, Bengt; Hunter, Tony; Palmer, Ruth

doi:10.1038/sj.embor.embor897

Cited by 110 publications

(137 citation statements)

References 26 publications

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“…30 Although MAM domains are thought to participate in cell--cell interactions, their significance in ALK function remains unclear. 15,16 Thus, the functional significance of MAM deletion in the truncated ALK is still elusive. As the deleted region of ALK detected in NB-1 cells is in close proximity to a ligandbinding domain (391--401 aa), this deletion may structurally alter the ligand-binding domain.…”

Section: Discussionmentioning

confidence: 99%

“…The deletion spanned 224 --318 amino acids (aa), including the N-terminal end of the first meprin A5 protein and receptor protein tyrosine phosphatase mu (MAM) domain (aa 264 --427) (Figure 1d). 15,16 We analyzed fulllength ALK cDNAs isolated from 71 primary neuroblastoma samples for possible nucleotide deletions using RT --PCR (Table 2), but no deletions were detected.…”

Section: Detection Of a Short-form Alk Protein In Nb-1 Cellsmentioning

confidence: 99%

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Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

et al. 2012

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Anaplastic lymphoma kinase (ALK) was originally identified from a rare subtype of non-Hodgkin's lymphomas carrying t(2;5)(p23;q35) translocation, where ALK was constitutively activated as a result of a fusion with nucleophosmin (NPM). Aberrant ALK fusion proteins were also generated in inflammatory fibrosarcoma and a subset of non-small-cell lung cancers, and these proteins are implicated in their pathogenesis. Recently, ALK has been demonstrated to be constitutively activated by gene mutations and/or amplifications in sporadic as well as familial cases of neuroblastoma. Here we describe another mechanism of aberrant ALK activation observed in a neuroblastoma-derived cell line (NB-1), in which a short-form ALK protein (ALK del2-3 ) having a truncated extracellular domain is overexpressed because of amplification of an abnormal ALK gene that lacks exons 2 and 3. ALK del2-3 was autophosphorylated in NB-1 cells as well as in ALK del2-3 -transduced cells and exhibited enhanced in vitro kinase activity compared with the wild-type kinase. ALK del2-3 -transduced NIH3T3 cells exhibited increased colony-forming capacity in soft agar and tumorigenicity in nude mice. RNAi-mediated ALK knockdown resulted in the growth suppression of ALK del2-3 -expressing cells, arguing for the oncogenic role of this mutant. Our findings provide a novel insight into the mechanism of deregulation of the ALK kinase and its roles in neuroblastoma pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Detection Of a Short-form Alk Protein In Nb-1 Cellsmentioning

confidence: 99%

Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

et al. 2012

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“…It is not clear whether Alk functions in hemocytes under normal conditions, but antibody staining suggested that the protein is expressed in hemocytes (data not shown). Recent experiments indicated that a functional Alk gene is crucial for gut formation (44), but because embryonic lethality of Alk mutant animals precludes study of the larval hemocyte population, a hemocyte function cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

A directed screen for genes involved in Drosophila blood cell activation

Zettervall

Ines

Williams

et al. 2004

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

313

400

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An attack by a parasitic wasp activates a vigorous cellular immune response in Drosophila larvae. This response is manifested by an increased number of circulating cells, the hemocytes, and by the appearance of a specialized class of hemocyte, the lamellocytes, which participate in the encapsulation and killing of the parasite. To study the molecular mechanisms of this response, we have overexpressed different genes in the hemocytes, by using the GAL4-upstream activating sequence system and a hemocytespecific Hemese-GAL4 driver. Multiple transgenes were tested, representing several important signaling pathways. We found that the proliferation response and the activation of lamellocyte formation are independent phenomena. A drastic increase in the number of circulating hemocytes is caused by receptor tyrosine kinases, such as Egfr, Pvr, and Alk, as well as by the downstream signaling components Ras85D and pointed, supporting the notion that the Ras-mitogen-activated protein kinase pathway regulates hemocyte numbers. In the case of Pvr and Alk, this phenotype also is accompanied by lamellocyte formation. By contrast, constitutively active hopscotch and hemipterous give massive activation of lamellocyte formation with little or no increase in total hemocyte numbers. This finding indicates that both the Jak͞Stat and the Jun kinase pathways affect lamellocyte formation. Still other signals, mediated by aop ACT , Toll 10b , and Rac1 expression, cause a simultaneous increase in lamellocyte and total cell numbers, and the same effect is seen when WNT signaling is suppressed. We conclude that the activation of a cellular response is complex and affected by multiple signaling pathways.

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“…Pleiotrophin and midkine, two heparinbinding growth factors, have been proposed to function as ALK ligand but these proteins fail to make a general consensus. This controversy is further supported by the genetic identification in Drosophila melanogaster of an ALK ligand, jelly belly (jeb), which has no similarities with pleiotrophin or midkine Loren et al, 2003). Finally, in the particular case of integrins, the ligand must be an immobilized substrate ligand to block apoptosis as, contrary to other DRs, soluble ligand is not sufficient to counteract cell death induction (Stupack, 2005).…”

Section: Role Of Ligand Bindingmentioning

confidence: 99%

Dependence receptors: a new paradigm in cell signaling and cancer therapy

2010

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Dependence receptors (DRs) now form a family of more than a dozen membrane receptors that are not linked by their structure, but by common functional traits. The most notable is their ability to trigger two opposite signaling pathways: in the presence of ligand, these receptors activate classic signaling pathways implicated in cell survival, migration and differentiation. In the absence of ligand, they do not stay inactive, rather they elicit an apoptotic signal. Thus, cells expressing this kind of receptor are dependent on the presence of ligand in the extracellular environment to survive. This review will recapitulate the increasing data regarding the molecular mechanisms associated with DRs, their potential implication during development, as well as their deregulation during tumorigenesis and, finally, their emergence as new possible therapeutic targets for cancer treatment.

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A crucial role for the Anaplastic lymphoma kinase receptor tyrosine kinase in gut development in Drosophila melanogaster

Cited by 110 publications

References 26 publications

Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

A directed screen for genes involved in Drosophila blood cell activation

Dependence receptors: a new paradigm in cell signaling and cancer therapy

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