The Receptor Tyrosine Kinase ARK Mediates Cell Aggregation by Homophilic Binding

Bellosta, Paola; Costa, Mario; Lin, Derek; Basilico, Claudio

doi:10.1128/mcb.15.2.614

Cited by 167 publications

(167 citation statements)

References 34 publications

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“…In addition, there is a structural basis for ligand-independent activation of AXL via homophilic cell adhesion (Heiring et al, 2004). Indeed, AXL overexpression may lead to AXL kinase-independent cell aggregation, which then results in autophospho- Fra-1 controls motility of bladder cancer cells AE Sayan et al rylation and receptor activation (Bellosta et al, 1995;Hafizi and Dahlbaeck 2006). Our data indicate that Fra-1-induced tumour cell motility, but not proliferation, is dependent on AXL expression levels.…”

Section: Discussionmentioning

confidence: 66%

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

et al. 2011

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Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscleinvasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels.

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Section: Discussionmentioning

confidence: 66%

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

et al. 2011

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“…Members of this family display IgG-like and fibronectin type III domains in their extracellular domain, features reminiscent of cell adhesion molecules; indeed, we were able to demonstrate that the ARK receptor can behave like a cell adhesion molecule by inducing cell aggregation through a homophelic mechanism (Bellosta et al, 1995). Recently Gas6 was identi®ed as a heterophilic ligand for ARK and Tyro3 receptors and c-mer, while Protein S was identi®ed as the ligand for the Tyro3 receptor (Nagata et al, 1996;Mark et al, 1996;Stitt et al, 1995;Varnum et al, 1995).…”

Section: Introductionmentioning

confidence: 74%

“…Similarly, a retrovirus encoding a gag-AXL fusion protein was only weakly transforming in NIH3T3 cells (Zhang et al, 1996). It is not known whether Gas6, the ARK heterophilic ligand, was expressed in the transformants, but a number of RTK have been shown to cause transformation when overexpressed, likely because high receptor surface density induces receptor dimerization and activation, a process which in this case could be also facilitated by ARK's ability to undergo homophilic binding (Bellosta et al, 1995). On the other hand, when we expressed constitutively Gas6 in ARK expressing NIH3T3 cells, we could not detect evidence of morphological transformation, ability to grow in low serum or at high densities, although we could show that ARK was activated in these cells.…”

Section: Discussionmentioning

confidence: 99%

Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation

et al. 1997

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ARK (AXL) is the prototype of a distinctive family of receptor tyrosine kinases which contain in their extracellular domains features reminiscent of cell adhesion molecules. ARK is capable of homophilic binding, which results in a degree of receptor activation, but can also be activated by a heterophilic ligand, Gas6, a member of the family of vitamin K dependent proteins that is preferentially expressed in quiescent cells. Since a number of tissues and cell lines express both ARK and Gas6, we studied the e ect of endogenous and exogenous Gas6 on the phenotype of ARK expressing cells. Here we show that constitutive expression of Gas6 in an NIH3T3 cell line that does not spontaneously express this protein does not result in cell transformation or uncontrolled growth, but protects from apoptosis induced by serum deprivation. Recombinant exogenous Gas6 was also capable of protecting cells from apoptosis at concentrations that did not result in signi®cant induction of DNA synthesis. Activation of ARK phosphorylation and a weak but signi®cant induction of MAP kinase activity accompanied the increased survival of cells treated with Gas6. The antiapoptotic e ect of ARK signaling was con®rmed by studies using ®broblasts from ARK knock-out mice, that showed that the absence of ARK resulted in higher levels of serum deprivation-induced apoptosis, that could not be rescued by the addition of Gas6. Interestingly ARK signaling protects from apoptosis induced by serum deprivation, myc overexpression, or by TNFa but not from u.v. irradiation or Staurosporine. These results suggest that a major function of Gas6 ± ARK signaling is that of increasing cell survival under conditions which do not allow cell proliferation.

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“…In addition, unique sequences within the kinase domain distinguish axl and its related kinases (sky and mer) from other type I RTKs. These structural ®ndings suggest that Axl family members may mediate both cell adhesion and intracellular signaling (Bellosta et al, 1995;Pulido et al, 1992).…”

Section: Introductionmentioning

confidence: 90%

Determinants for transformation induced by the Axl receptor tyrosine kinase

et al. 1998

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The Axl receptor tyrosine kinase is a transforming oncogene in NIH3T3 cells. In order to de®ne structural requirements of the Axl receptor necessary for transformation we passaged recombinant retroviruses carrying the axl cDNA in NIH3T3 cells, generating randomly mutated axl variants. Using this strategy, we have isolated three axl viral strains (1B1, SV8, and FFa4) that show augmented 3T3 cell transforming capacity associated with elevated p140 Axl . Upon sequencing, the 1B1 and SV8 proviruses possessed only silent mutations, making p140 Axl overexpression the most likely explanation for their increased transformation activity. However, the characterization of FFa4 revealed a deletion of sequences encoding the carboxy-terminal 45 amino acids leading to the generation of a chimeric transcript comprised of a truncated Axl receptor with a segment of the 3' UTR region. Mutational analysis revealed that the transforming activity of FFa4 was speci®c to the formation of the chimeric receptor rather than to the carboxyl-terminal truncation. Intriguingly, none of the viral strains were able to transform the murine cell lines NR-6 and 32D despite equivalent expression of surface p140 Axl protein. Further analysis showed that Axl's transforming potential is dependent on the host cell type, the presence of a putative pp190 as a facilitator for transformation, and the level of p140 Axl expression. Taken together, these results underscore the complexity of Axl biology which is dependent on receptor stoichiometry and the cellular background.

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The Receptor Tyrosine Kinase ARK Mediates Cell Aggregation by Homophilic Binding

Cited by 167 publications

References 34 publications

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL

Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation

Determinants for transformation induced by the Axl receptor tyrosine kinase

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