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

Goruppi, Sandro; Ruaro, Elisabetta; Varnum, Brian; Schneider, Claudio

doi:10.1128/mcb.17.8.4442

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

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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TAM receptor signaling leads to activation of NF-kB, which is thought to promote cell survival in fibroblasts and endothelial cells.
“This also leads to activation of NF-kB, which is thought to promote cell survival in fibroblasts and endothelial cells [147, 151, 152].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [151]
The Abstract (p. 4442) reports that Gas6–Axl signaling prevents apoptosis in NIH 3T3 fibroblasts and implicates PI3K-dependent signaling and Src in that survival effect. Our copy does not report NF-κB activation or a survival effect in endothelial cells (searched: NF-κB and endothelial cells). (LLM, conf=0.84)
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Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases
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Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer
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Targeting Axl and Mer Kinases in Cancer
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Phosphoproteomic analysis of Her2/neu signaling and inhibition
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Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor
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The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target
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TNF-α, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages
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GAS6 Induces Axl-mediated Chemotaxis of Vascular Smooth Muscle Cells
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The physiology of vitamin K nutriture and vitamin K‐dependent protein function in atherosclerosis
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AXL-Driven EMT State as a Targetable Conduit in Cancer
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Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells
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The receptor tyrosine kinase Axl in cancer: Biological functions and therapeutic implications
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Both protein S and Gas6 stimulate outer segment phagocytosis by cultured rat retinal pigment epithelial cells
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The receptor tyrosine kinase Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target
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Vitamin K‐Dependent Carboxylation
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Growth Arrest-Specific Gene 6 (Gas6)/Adhesion Related Kinase (Ark) Signaling Promotes Gonadotropin-Releasing Hormone Neuronal Survival via Extracellular Signal-Regulated Kinase (ERK) and Akt
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Gas6 inhibits apoptosis in vascular smooth muscle: role of Axl kinase and Akt
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Expression of Receptor Tyrosine Kinase Axl and its Ligand Gas6 in Rheumatoid Arthritis
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Frankincense oil derived from Boswellia carteri induces tumor cell specific cytotoxicity
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Gas6/Axl pathway promotes tumor invasion through the transcriptional activation of Slug in hepatocellular carcinoma
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The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia
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A Single Amino Acid Substitution in the v-Eyk Intracellular Domain Results in Activation of Stat3 and Enhances Cellular Transformation
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Expression of the receptor protein-tyrosine kinases Tyro-3, Axl, and Mer in the developing rat central nervous system
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Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein
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Gas6 receptors Axl, Sky and Mer enhance platelet activation and regulate thrombotic responses
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Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras
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Growth arrest‐specific gene 6 and Axl signaling enhances gastric cancer cell survival via Akt pathway
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Gas6 Anti-apoptotic Signaling Requires NF-κB Activation
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SIROLIMUS (RAPAMYCIN) HALTS AND REVERSES PROGRESSION OF ALLOGRAFT VASCULAR DISEASE IN NON-HUMAN PRIMATES1
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Signaling Pathways Mediating Insulin‐Stimulated Glucose Transport
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Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells
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Growth Arrest-Specific Gene 6 (gas6) and Vascular Hemostasis
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Biological Effects of c-Mer Receptor Tyrosine Kinase in Hematopoietic Cells Depend on the Grb2 Binding Site in the Receptor and Activation of NF-κB
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The human receptor tyrosine kinase Axl gene – promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation
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Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease
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Osteopontin induces multiple changes in gene expression that reflect the six “hallmarks of cancer” in a model of breast cancer progression
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TheGrowth Arrest-SpecificGene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway
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Growth arrest-specific gene 6 (GAS6)
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Essential role of Gas6 for glomerular injury in nephrotoxic nephritis
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Survival and Migration of Human Dendritic Cells Are Regulated by an IFN-α-Inducible Axl/Gas6 Pathway
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Plasma concentrations of Gas6 and sAxl correlate with disease activity in systemic lupus erythematosus
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Expression of the Receptor Tyrosine Kinase Axl Promotes Ocular Melanoma Cell Survival
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ABL Regulation by AXL Promotes Cisplatin Resistance in Esophageal Cancer
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The Gas6/Axl System
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The role of Axl in drug resistance and epithelial-to-mesenchymal transition of non-small cell lung carcinoma.
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Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis
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RETRACTED ARTICLE: Soluble Axl Is Generated by ADAM10-Dependent Cleavage and Associates with Gas6 in Mouse Serum
Budagian, V., Bulanova, E., Orinska, Z., Duitman, E. H., Brandt, K., Ludwig, A., Hartmann, D., Lemke, G., Säftig, P., & Bulfone‐Paus, S. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9324-9339.2005 · Cited by 84 · see citing works
Retracted
Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors
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Axl/Phosphatidylinositol 3-Kinase Signaling Inhibits Mineral Deposition by Vascular Smooth Muscle Cells
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Growth Arrest–Specific Protein 6 Is Hepatoprotective Against Murine Ischemia/Reperfusion Injury
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Essential role of Gas6 for glomerular injury in nephrotoxic nephritis
Yanagita, M., Ishimoto, Y., Arai, H., Nagai, K., Ito, T., Nakano, T., Salant, D. J., Fukatsu, A., Doi, T., & Kita, T. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0214861 · Cited by 78 · see citing works
Rho-dependent Regulation of Cell Spreading by the Tetraspan Membrane Protein Gas3/PMP22
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Gas6 Induces Growth, β-Catenin Stabilization, and T-Cell Factor Transcriptional Activation in Contact-Inhibited C57 Mammary Cells
Goruppi, S., Chiaruttini, C., Ruaro, M. E., Varnum, B. C., & Schneider, C. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.3.902-915.2001 · Cited by 77 · see citing works
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The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development
Park, I., Giovenzana, C., Hughes, T. L., Yu, J., Trotta, R., & Caligiuri, M. A. (2008) · Blood · doi:10.1182/blood-2008-05-157073 · Cited by 74 · see citing works
Signaling pathways and late‐onset gene induction associated with renal mesangial cell hypertrophy
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A promiscuous liaison between IL‐15 receptor and Axl receptor tyrosine kinase in cell death control
Budagian, V., Bulanova, E., Orinska, Z., Thon, L., Mamat, U., Bellosta, P., Basilico, C., Adam, D., Paus, R., & Bulfone‐Paus, S. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600874 · Cited by 75 · see citing works
Retracted
Vitamin K‐Dependent Actions of Gas6
Bellido‐Martín, L., & de Frutos, P. G. (2008) · Vitamins and hormones · doi:10.1016/s0083-6729(07)00009-x · Cited by 73 · see citing works
Growth arrest-specific protein 6 plasma concentrations during septic shock
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Induction, regulation, and biologic function of Axl receptor tyrosine kinase in Kaposi sarcoma
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Mechanism of Inhibitory Effect of Warfarin on Mesangial Cell Proliferation
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Skipping of exon 10 in Axl pre-mRNA regulated by PTBP1 mediates invasion and metastasis process of liver cancer cells
Shen, L., Lei, S., Zhang, B., Li, S., Huang, L., Czachor, A., Breitzig, M., Gao, Y., Huang, M., Mo, X., et al. (2020) · Theranostics · doi:10.7150/thno.42010 · Cited by 70 · see citing works
The Dual Role of TAM Receptors in Autoimmune Diseases and Cancer: An Overview
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Growth arrest specific protein 6/Axl signaling in human inflammatory renal diseases
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Ontogeny of GnRH and olfactory neuronal systems in man: novel insights from the investigation of inherited forms of Kallmann?s syndrome
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Increased Tubular Proliferation as an Adaptive Response to Glomerular Albuminuria
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Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases Axl and Sky in human uterine endometrial cancers
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Axl Is a Prognostic Marker in Oral Squamous Cell Carcinoma
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Axl-Gas6 Interaction Counteracts E1A-Mediated Cell Growth Suppression and Proapoptotic Activity
Lee, W.-P., Liao, Y., Robinson, D. R., Kung, H.-J., Liu, E. T., & Hung, M. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.12.8075 · Cited by 63 · see citing works
Genetic loss of Gas6 induces plaque stability in experimental atherosclerosis
Lutgens, E., Tjwa, M., de Frutos, P. G., Wijnands, E., Beckers, L., Dahlbäck, B., Daemen, M. J. A. P., Carmeliet, P., & Moons, L. (2008) · The Journal of Pathology · doi:10.1002/path.2381 · Cited by 61 · see citing works
Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells
Tian, Y., Zhang, Z., Miao, L., Yang, Z., Yang, J., Wang, Y., Qian, D., Cai, H., & Wang, Y. (2016) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.3727/096504016x14648701447814 · Cited by 61 · see citing works
Gas 6 promotes Axl-mediated survival in pulmonary endothelial cells
Healy, A. M., Schwartz, J. J., Zhu, X., Herrick, B., Varnum, B. C., & Farber, H. W. (2001) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2001.280.6.l1273 · Cited by 60 · see citing works
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The Gas6/TAM System and Multiple Sclerosis
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Adhesion-Related Kinase Induction of Migration Requires Phosphatidylinositol-3-Kinase and Ras Stimulation of Rac Activity in Immortalized Gonadotropin-Releasing Hormone Neuronal Cells
Nielsen‐Preiss, S. M., Allen, M. P., Xu, M., Linseman, D. A., Pawlowski, J. E., Bouchard, R. J., Varnum, B. C., Heidenreich, K. A., & Wierman, M. E. (2007) · Endocrinology · doi:10.1210/en.2007-0039 · Cited by 59 · see citing works
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TAM receptors in cardiovascular disease
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Cytoplasmic ACK1 Interaction with Multiple Receptor Tyrosine Kinases Is Mediated by Grb2
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Mechanistic and Functional Studies of the Interaction of a Proline-rich Antimicrobial Peptide with Mammalian Cells
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Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence
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Yap/Taz promote the scavenging of extracellular nutrients through macropinocytosisPreprint
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Gas6–Axl Receptor Signaling Is Regulated by Glucose in Vascular Smooth Muscle Cells
Cavet, M. E., Smolock, E. M., Öztürk, O. H., WORLD, C., Pang, J., Konishi, A., & Berk, B. C. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.162693 · Cited by 56 · see citing works
Role of Gas6/Axl signaling in lens epithelial cell proliferation and survival
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Vitamin K-dependent Proteins in the Developing and Aging Nervous System
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Gas6 attenuates lipopolysaccharide‑induced TNF‑α�expression and apoptosis in H9C2 cells through NF‑κB and�MAPK inhibition via the Axl/PI3K/Akt pathway
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gas2Is a Multifunctional Gene Involved in the Regulation of Apoptosis and Chondrogenesis in the Developing Mouse Limb
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The Phosphatidylinositol 3-Kinase/Akt Signaling Pathway Modulates the Endocrine Differentiation of Trophoblast Cells
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Requirement of phosphatidylinositol
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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
Health Sciences › Medicine › Oncology › 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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