Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site

Braunger, Jürgen; Schleithoff, Lothar; Schulz, Ansgar; Kessler, Heidi; Lammers, Reiner; Ullrich, Axel; Bartram, Claus R.; Janssen, Johannes W.G.

doi:10.1038/sj.onc.1201123

Cited by 153 publications

(151 citation statements)

References 40 publications

(58 reference statements)

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“…Such cells express Rse/Tyro3, a member of the family with similar binding a nity for Gas6 (Mark et al, 1996), possibly suggesting that Rse/Tyro3 activation is not able to protect cells from cell death and that full Gas6 survival e ect requires Axl RTK. It is interesting to note that even though the Axl cytoplasmic domain contains several tyrosines, with the potential binding sites for adapters, its signalling was shown to be mediated mainly by a multi-substrate docking site (Braunger et al, 1997) with a consensus binding site for PI3K Goruppi et al, 1997). In the present report, we have identi®ed targets downstream of Gas6-activated PI3K that are required for its antiapoptotic signalling on serum starved NIH3T3 cells.…”

Section: Discussionmentioning

confidence: 62%

“…Consistent with this, Axl cytoplasmic domain was shown to bind Grb2 protein (Braunger et al, 1997;Fridell et al, 1995) and Gas6 addition to serum starved cells induced a signi®cant activation of Shc (Goruppi et al, 1996). To have further insights on the role of Ras in Gas6 signalling, we analysed the e ects of microinjection of two well characterized anti Ras monoclonal antibodies on Gas6-induced mitogenesis.…”

Section: Ras Blocking Antibodies Ablate Gas6-induced Mitogenesismentioning

confidence: 70%

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

et al. 1999

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Section: Discussionmentioning

confidence: 62%

Section: Ras Blocking Antibodies Ablate Gas6-induced Mitogenesismentioning

confidence: 70%

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

et al. 1999

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“…Gas6 was first discovered as an upregulated gene in growth-arrested cells (12), and further studies with Gas6 signaling suggested its role in cell survival (13,14), proliferation (15,16), stimulation of cell migration (17), and cell-cell adhesion through Axl (18). Intracellular signaling of Axl is also activated by its homophilic and heterophilic interactions (19), mediated mainly by a multisubstrate docking site (20). Overexpression of Axl can transform fibroblasts even in the absence of a ligand (21), this is at least in part being mediated by Gas6/Axl-induced activation of mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase signaling.…”

Section: Introductionmentioning

confidence: 99%

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Mudduluru

Vajkoczy

Allgayer

2010

Molecular Cancer Research

117

129

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Myeloid zinc finger 1 (MZF1) is a member of the SCAN domain family transcription factors that form dimers through their highly conserved SCAN motifs. Silencing of MZF1 inhibits cell proliferation, and abnormal expression of MZF1 results in cancer development. However, a potential role of MZF1 in metastasis remains unclear. Axl is a receptor tyrosine kinase and was first identified as a transforming gene in chronic myeloid leukemia. Axl overexpression induces proliferation, migration, and invasion and is highly expressed in different human cancers. In this study, we show that overexpression of MZF1 induces migration and invasion in colorectal (Rko, SW480) and cervical (HeLa) cancer cells. In addition, we show that MZF1 binds to the Axl promoter, transactivates promoter activity, and enhances Axl-mRNA and protein expression in a dose-dependent manner. In vitro, sh-RNA knockdown of Axl reduced MZF1-induced migration and invasion in HeLa and Rko cells (P = 0.05). Additionally, Rko cells overexpressing MZF1 showed increased tumor formation and liver metastasis in the chicken-embryo-metastasis assay in vivo. Furthermore, the expression of MZF1 and Axl was significantly higher in resected colorectal tumors compared with corresponding normal tissues (P = 0.02; P = 0.05), and MZF1 expression was positively correlated with Axl gene expression in tumor tissues (P < 0.01). Taken together, this is the first study to show that MZF1 induces invasion and in vivo metastasis in colorectal and cervical cancer, at least in part by regulating Axl gene expression. Mol Cancer Res; 8(2); 159-69. ©2010 AACR.

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“…3a). Three (AXL, FN1 and IRS1) of these four genes are on the KEGG PI3K-Akt pathway 45,46 . Further, among all transcription factors, STAT3 and NFKB1 were found to have the lowest levels of phosphorylation among patients with mutations in AAM pathway genes; the levels among patients without mutations were significantly (Po0.05) higher (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival

et al. 2014

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The arachidonic acid metabolism (AAM) pathway promotes tumour progression. Chemical inhibitors of AAM pathway prolong post-treatment survival of cancer patients. Here we test whether non-synonymous somatic mutations in genes of this pathway, acting as natural inhibitors, increase post-treatment survival. We identify loss-of-function somatic mutations in 15 (18%) of 84 treatment-naïve oral cancer patients by whole-exome sequencing, which we map to genes of AAM pathway. Patients (n ¼ 53) who survived Z12 months after surgery without recurrence have significantly (P ¼ 0.007) higher proportion (26% versus 3%) of mutations than those who did not (n ¼ 31). Patients with mutations have a significantly (P ¼ 0.003) longer median disease-free survival (24 months) than those without (13 months). Compared with the presence of a mutation, absence of any mutation increases the hazard ratio for death (11.3) significantly (P ¼ 0.018).

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Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site

Cited by 153 publications

References 40 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

Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer

Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival

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