Cited by 192PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingCytokine Signaling Pathways and Interactions

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Requirement of Phosphatidylinositol 3-Kinase-Dependent Pathway and Src for Gas6-Axl Mitogenic and Survival Activities in NIH 3T3 Fibroblasts

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Goruppi, Sandro, Ruaro, Elisabetta, Varnum, Brian, Schneider, Claudio·1997·Molecular and Cellular Biology

DOI 10.1128/mcb.17.8.4442PMC PMC232298

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Abstract

Gas6 is a secreted protein previously identified as the ligand of the Axl receptor tyrosine kinase. We have shown that Gas6 is able to induce cell cycle reentry of serum-starved NIH 3T3 cells and to efficiently prevent apoptosis after complete growth factor removal, a survival effect uncoupled from Gas6-induced mitogenesis. Here we report that the mitogenic effect of Gas6 requires phosphatidylinositol 3-kinase (PI3K) activity since it is abrogated both by the specific inhibitor wortmannin and by overexpression of the dominant negative P13K p85 subunit. Consistently, Gas6 activates the P13K downstream targets S6K and Akt, whose activation is abrogated by addition of wortmannin. Moreover, rapamycin treatment blocks Gas6-induced entry into the S phase of serum-starved NIH 3T3 cells. We also demonstrate the requirement of Src tyrosine kinase for Gas6 signalling since stable or transient expression of a catalytically inactive form of Src significantly inhibited Gas6-stimulated entry into the S phase. Accordingly, Gas6 addition to serum-starved NIH 3T3 cells causes activation of the intrinsic Src kinase activity. When specifically analyzed in a survival assay, these elements were found to be required for the survival effect of Gas6. Taken together, the evidence presented here identifies elements involved in the Gas6 transduction pathway that are responsible for its antiapoptotic effect and suggests that Src is involved in the events regulating cell survival.

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Authors: Goruppi, S., Ruaro, E., Varnum, B., & Schneider, C.
Affiliations: Amgen (United States) (US)
Consorzio Interuniversitario per le Biotecnologie (IT)
University of Udine (IT)
ORCID: Goruppi, Sandro
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 1997-08
Volume: 17
Issue: 8
Pages: 4442-4453
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.17.8.4442
PMC: PMC232298
OpenAlex: W2119376722
Cited by: 191
References: 70
Citations by year: 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 6 · 2016: 10 · 2015: 5 · 2014: 9 · 2013: 9 · 2012: 4
FWCI: 2.49
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Institutional Research Information System (University of Udine) (submittedVersion)
Funders: Associazione Italiana per la Ricerca sul Cancro
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Keywords: Gas6, AXL receptor, phosphatidylinositol 3-kinase, Src kinase, cell survival signaling, mitogenesis, apoptosis inhibition, S6K, Akt, wortmannin, rapamycin, cell cycle re-entry, S phase entry, NIH3T3 cells, receptor tyrosine kinase signaling
MeSH terms: Wortmannin, Axl Receptor Tyrosine Kinase, Growth Arrest-Specific Protein 6, Androstadienes, Animals, Cell Survival, Enzyme Activation, Enzyme Inhibitors, Mitogens, Phosphorylation, Polyenes, Proteins, Proto-Oncogene Proteins, Receptors, Cell Surface, Signal Transduction, Oncogene Proteins, Proto-Oncogene Proteins pp60(c-src), 3T3 Cells, Protein Serine-Threonine Kinases, Phosphotransferases (Alcohol Group Acceptor), Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Sirolimus, Receptor Protein-Tyrosine Kinases, Intercellular Signaling Peptides and Proteins, Mice

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Requirement of Phosphatidylinositol 3-Kinase-Dependent Pathway and Src for Gas6-Axl Mitogenic and Survival Activities in NIH 3T3 Fibroblasts

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