FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCɛ, B-Raf and S6K2

Pardo, Olivier E.; Wellbrock, Claudia; Khanzada, Umme K.; Aubert, M; Arozarena, Imanol; Davidson, Sally; Bowen, Frances; Parker, Peter J.; Filonenko, Valeriy; Gout, Ivan; Sebire, Neil J.; Marais, Richard; Downward, Julian; Seckl, Michael J.

doi:10.1038/sj.emboj.7601198

Cited by 172 publications

(180 citation statements)

References 39 publications

Supporting

Mentioning

175

Contrasting

Unclassified

Order By: Relevance

“…This has partly been elucidated, because S6K2 but not S6K1 has been shown to be localized to centrosomes in cells (54). In addition, it has also been reported that S6K2 but not S6K1 is able to regulate cell survival (20). Similarly, S6K1 but not S6K2 is involved with intron-containing RNA splicing through its association with SKAR (25).…”

Section: Discussionmentioning

confidence: 99%

“…More recently, it was also demonstrated that the mTOR kinase and S6K2 have the ability to regulate cell proliferation and cell cycle progression (15,16). Most studies on S6K regulation and function focused on S6K1, establishing that S6K1 is able to regulate a number of key cellular processes, including insulin metabolism (17,18), cell survival (19,20), translation (21)(22)(23)(24), and more recently RNA splicing (25). Inactive S6K1 was reported to localize on the translational preinitiation complex through its interaction with eukaryotic initiation factor 3.…”

mentioning

confidence: 99%

“…Gene amplification and overexpression at mRNA and protein levels were reported for both S6K1 and S6K2 in various malignancies. Interestingly, overexpression and higher nuclear localization of S6K2 were observed in human breast cancer (14) and also were linked to pro-survival and chemoresistance signaling in small cell lung cancer (20).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Involvement of Heterogeneous Ribonucleoprotein F in the Regulation of Cell Proliferation via the Mammalian Target of Rapamycin/S6 Kinase 2 Pathway

Goh

Pardo

Michael

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The S6 kinases (S6Ks) have been linked to a number of cellular processes, including translation, insulin metabolism, cell survival, and RNA splicing. Signaling via the phosphotidylinositol 3-kinase and mammalian target of rapamycin (mTOR) pathways is critical in regulating the activity and subcellular localization of S6Ks. To date, nuclear functions of both S6K isoforms, S6K1 and S6K2, are not well understood. To better understand S6K nuclear roles, we employed affinity purification of S6Ks from nuclear preparations followed by mass spectrometry analysis for the identification of novel binding partners. In this study, we report that in contrast to S6K1, the S6K2 isoform specifically associates with a number of RNA-binding proteins, including heterogeneous ribonucleoproteins (hnRNPs). We focused on studying the mechanism and physiological relevance of the S6K2 interaction with hnRNP F/H. Interestingly, the S6K2-hnRNP F/H interaction was not affected by mitogenic stimulation, whereas mTOR binding to hnRNP F/H was induced by serum stimulation. In addition, we define a new role of hnRNP F in driving cell proliferation, which could be partially attenuated by rapamycin treatment. S6K2-driven cell proliferation, on the other hand, could be blocked by small interfering RNA-mediated down-regulation of hnRNP F. These results demonstrate that the specific interaction between mTOR and S6K2 with hnRNPs is implicated in the regulation of cell proliferation.Regulation of cellular processes by extracellular stimuli, such as growth factors and nutrients, is an essential process in cell size and cell cycle control. The mammalian target of rapamycin (mTOR) 2 is a key regulator of cellular signaling and is highly dependent on the presence of nutrients, as well as growth factor-stimulated signaling from the phosphotidylinositol 3-kinase (PI3K) pathway. Activation of PI3K by a number of growth factor receptors leads to increased levels of phosphatidylinositol 3,4,5-triphosphate (1), a secondary messenger that recruits downstream kinases, such as 3-phosphoinositide-dependent kinase 1 (PDK1), to the plasma membrane (2). Membrane-associated PDK1 in turn phosphorylates and activates Akt at the T loop (3, 4), whereas activated Akt phosphorylation of tuberous sclerosis complex 2 (TSC2) blocks its inhibitory role in mTOR signaling (5, 6). TSC2 forms a heterodimer with TSC1, which as a complex acts as a GTPase activator toward the small GTPase, Rheb (Ras homolog enriched in brain) (7,8). Rheb associates directly with the catalytic domain of mTOR and activates it by antagonizing FKBP38, the proposed endogenous inhibitor of mTOR (9). Activated mTOR with its interacting partner protein Raptor, as part of the mTOR complex I (mTORC1) is able to phosphorylate S6Ks (at Thr 389 in S6K1 and Thr 388 in S6K2) (10). This early phosphorylation event is required for subsequent phosphorylation by PDK1 of Thr 229 and Thr 228 in the activation loops of S6K1 and S6K2, respectively (11). Phosphorylation by both mTORC1 and PDK1 leads to S6K activation, resul...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Involvement of Heterogeneous Ribonucleoprotein F in the Regulation of Cell Proliferation via the Mammalian Target of Rapamycin/S6 Kinase 2 Pathway

Goh

Pardo

Michael

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In contrast, although ectopic expression of PKCε resulted in decreased Bax translocation to mitochondria in melanoma cell lines there was no association between PKCε and Bax [31]. Recent work by Pardo and colleagues showed that a higher expression level of PKCε in small cell lung cancer (SCLC) was associated with higher Bcl-X L and X-linked inhibitor of apoptosis (XIAP) protein levels [137]. Furthermore, adenoviral overexpression of PKCε in H69 cells protected them from VP-16-induced death and this was correlated with increased Bcl-X L and XIAP protein levels.…”

Section: Pkcε and Bcl-2 Family: Many Partners In The Dance Of Deathmentioning

confidence: 99%

Protein kinase Cε makes the life and death decision

Basu

Sivaprasad

2007

Cellular Signalling

144

152

View full text Add to dashboard Cite

Cancer is caused by dysregulation in cellular signaling systems that control cell proliferation, differentiation and cell death. Protein kinase C (PKC), a family of serine/threonine kinases, plays an important role in the growth factor signal transduction pathway. PKCε, however, is the only PKC isozyme that has been considered as an oncogene. It can contribute to malignancy by enhancing cell proliferation or by inhibiting cell death. This review focuses on how PKCε collaborates with other signaling pathways, such as Ras/Raf/ERK and Akt, to regulate cell survival and cell death. We have also discussed how PKCε mediates is antiapoptotic signal by altering the level or function of proand antiapoptotic Bcl-2 family members.

show abstract

“…These experiments establish a high degree of specificity of the reported compounds selectively blocking FGF2 as a substrate of Tec kinase. The potential of the reported small molecule inhibitors as lead compounds for drug development is discussed, in particular with regard to tumor-induced angiogenesis (41,42) and the role of FGF2 as a tumor cell survival factor (43)(44)(45)(46).…”

mentioning

confidence: 99%

Small Molecule Inhibitors Targeting Tec Kinase Block Unconventional Secretion of Fibroblast Growth Factor 2

Venuta

Wegehingel

Sehr

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Fibroblast growth factor 2 (FGF2) is a potent mitogen promoting both tumor cell survival and tumor-induced angiogenesis. It is secreted by an unconventional secretory mechanism that is based upon direct translocation across the plasma membrane. Key steps of this process are (i) phosphoinositide-dependent membrane recruitment, (ii) FGF2 oligomerization and membrane pore formation, and (iii) extracellular trapping mediated by membrane-proximal heparan sulfate proteoglycans. Efficient secretion of FGF2 is supported by Tec kinase that stimulates membrane pore formation based upon tyrosine phosphorylation of FGF2. Here, we report the biochemical characterization of the direct interaction between FGF2 and Tec kinase as well as the identification of small molecules that inhibit (i) the interaction of FGF2 with Tec, (ii) tyrosine phosphorylation of FGF2 mediated by Tec in vitro and in a cellular context, and (iii) unconventional secretion of FGF2 from cells. We further demonstrate the specificity of these inhibitors for FGF2 because tyrosine phosphorylation of a different substrate of Tec is unaffected in their presence. Building on previous evidence using RNA interference, the identified compounds corroborate the role of Tec kinase in unconventional secretion of FGF2. In addition, they are valuable lead compounds with great potential for drug development aiming at the inhibition of FGF2-dependent tumor growth and metastasis.Although the majority of secretory proteins carry signal peptides for endoplasmic reticulum/Golgi-dependent secretion, a set of important growth factors and cytokines involved in tumor-induced angiogenesis and inflammatory responses makes use of alternative routes. These processes have collectively been termed "unconventional protein secretion" (1-5). FGF2 and IL1␤ are prominent examples for secretory proteins that make use of such pathways (4 -12). The molecular mechanism by which IL1␤ is secreted from cells is debated and may differ in some aspects between various kinds of immune cells (4,5,10,(13)(14)(15)(16). By contrast, the mechanism of the unconventional secretory pathway of FGF2 is emerging with great molecular detail (12). It is based upon direct translocation of folded species of FGF2 across plasma membranes (9,(17)(18)(19)(20). Hallmarks of this process are (i) FGF2 recruitment at the inner leaflet of the plasma membrane mediated by the phosphoinositide PI(4,5)P 2 2 (9, 21, 22), (ii) FGF2 oligomerization and membrane pore formation (11,12,23,24), and (iii) extracellular trapping of FGF2 mediated by membrane-proximal heparan sulfate proteoglycans (1,2,25,26). Recently, these hallmarks of FGF2 secretion have also been implicated in unconventional secretion of HIV-Tat (HIV trans-activator of transcription) (12, 27-30). Based on a genome-wide RNAi screening approach, two additional factors physically associated with the plasma membrane have been identified to play a role in FGF2 secretion, Tec kinase (9, 11, 12, 24, 31) and ATP1A1 (12, 32-34), the ␣ subunit of the Na/K-ATPase (35). Although t...

show abstract

FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCɛ, B-Raf and S6K2

Cited by 172 publications

References 39 publications

Involvement of Heterogeneous Ribonucleoprotein F in the Regulation of Cell Proliferation via the Mammalian Target of Rapamycin/S6 Kinase 2 Pathway

Involvement of Heterogeneous Ribonucleoprotein F in the Regulation of Cell Proliferation via the Mammalian Target of Rapamycin/S6 Kinase 2 Pathway

Protein kinase Cε makes the life and death decision

Small Molecule Inhibitors Targeting Tec Kinase Block Unconventional Secretion of Fibroblast Growth Factor 2

Contact Info

Product

Resources

About