Vascular Smooth Muscle Cell-derived, Gla-containing Growth-potentiating Factor for Ca2+-mobilizing Growth Factors

Nakano, Toru; Higashino, Kenichi; Kikuchi, Norihisa; Kishino, Junji; Nomura, Koji; Fujita, Hiroko; Ohara, Osamu; Arita, Hitoshi

doi:10.1074/jbc.270.11.5702

Cited by 176 publications

(180 citation statements)

References 17 publications

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“…More recent studies have shown that Gas6 can similarly bind and activate Rse/Sky and Mer RTK, although with lower a nity (Chen et al, 1997;Mark et al, 1996;Nagata et al, 1996;Ohashi et al, 1995). Gas6 was shown to act as a growth factor for ®broblasts, Schwann cells, chondrocytes, thyroid and vascular smooth muscle cells (Goruppi et al, 1996;Li et al, 1996;Loeser et al, 1997;Nakano et al, 1995;Tanaka et al, 1998). In most of the cellular systems Gas6 has been reported to protect cells from apoptosis independently of its growth stimulating activity (Avanzi et al, 1997;Bellosta et al, 1997;Goruppi et al, 1996;, therefore suggesting that induction of proliferation and prevention of apoptosis could involve elements in distinct (parallel) pathways.…”

Section: Introductionmentioning

confidence: 99%

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

et al. 1999

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Section: Introductionmentioning

confidence: 99%

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

et al. 1999

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“…Surprisingly, however, the Axl ligand, GAS-6, is only a weak mitogen in a restricted range of tissue such as 3T3, Schwann, and vascular smooth muscle cells (Goruppi et al, 1996;Gasic et al, 1992;Li et al, 1996) and appears to play a greater role in modulating cellular responses to other factors such as thrombin and angiotensin II (Nakano et al, 1995). That a ligand shows little mitogenic activity when interacting with a RTK with transforming function has been seen in the Eph receptor tyrosine kinase family (Brambilla et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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 pleotropic effects of Gas6-Axl interactions in different tissues may be summarized as follows. In vascular smooth muscle, Gas6 was initially purified as a mediator of vascular smooth muscle proliferation (34). Later studies showed Axl upregulation at sites of vascular injury, suggesting a role for this receptor in vascular remodeling (29).…”

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confidence: 99%

Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells

Hasanbasic

Cuerquis²,

Varnum³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

129

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Gas6 is a γ-carboxylated ligand for the receptor tyrosine kinase Axl. Gas6-Axl interactions can rescue endothelial cells from apoptosis, and this study examined the intracellular signaling mechanisms responsible for this phenomenon. Using flow cytometry, we first confirmed that Gas6 can abrogate apoptosis induced by serum starvation of primary cultures of human umbilical vein endothelial cells (HUVECs). This effect is mediated through phosphorylation of the serine-threonine kinase Akt, with maximal phosphorylation observed after 4 h of treatment with 100 ng/ml Gas6. Inhibition of Akt phosphorylation and abrogation of gas6-mediated survival of HUVECs by wortmannin implicated phosphatidylinositol 3-kinase as the mediator of Akt phosphorylation. Dominant negative Akt constructs largely abrogated the protective effect of Gas6 on HUVECs, underscoring the importance of Akt activation in Gas6-mediated survival. Several downstream regulators of this survival pathway were identified in HUVECs, namely, NF-κB as well as the antiapoptotic and proapoptotic proteins Bcl-2 and caspase 3, respectively. We showed that NF-κB is phosphorylated early after Gas6 treatment as evidenced by doublet formation on Western blotting. As well, the level of Bcl-2 protein increased, supporting the notion that the Bcl-2 antiapoptotic pathway is stimulated. The levels of expression of the caspase 3 activation products p12 and p20 decreased with Gas6 treatment, consistent with a reduction in proapoptotic caspase 3 activation. Taken together, these experiments provide new information about the mechanism underlying Gas6 protection from apoptosis in primary endothelial cell cultures.

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Vascular Smooth Muscle Cell-derived, Gla-containing Growth-potentiating Factor for Ca2+-mobilizing Growth Factors

Cited by 176 publications

References 17 publications

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

Determinants for transformation induced by the Axl receptor tyrosine kinase

Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells

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