Fibroblast growth factor (FGF) signaling through PI 3-kinase and Akt/PKB is required for embryoid body differentiation

Chen, Yali; Li, Xiaofeng; Eswarakumar, Veraragavan P.; Seger, Rony; Lonai, Peter

doi:10.1038/sj.onc.1203726

Cited by 120 publications

(100 citation statements)

References 48 publications

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“…is independent of the well established PI3K-Akt signaling pathway utilized by most peptide growth factors such as IGF-1, EGF, and other FGFs (25)(26)(27)(28). Instead, our data provide evidence to show that activation of S6K1 is directly mediated by mTOR.…”

Section: Discussioncontrasting

confidence: 45%

“…Furthermore, phosphatidylinositol 3-kinase (PI3K)/Akt/p70 ribosomal S6 kinase (S6K1) cascade also play important roles in mediating FGFR signaling. Activation of PI3K by FGF-FGFRs has been demonstrated in studies using biochemical, pharmacological, and genetic approaches (25)(26)(27)(28). Results from these studies suggested that PI3K can be activated directly via association with FRS or indirectly via an Erk-dependent pathway (27,29).…”

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confidence: 99%

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The Mammalian Target of Rapamycin-p70 Ribosomal S6 Kinase but Not Phosphatidylinositol 3-Kinase-Akt Signaling Is Responsible for Fibroblast Growth Factor-9-induced Cell Proliferation

Wing

Chen

Chuang

et al. 2005

Journal of Biological Chemistry

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Fibroblast growth factor-9 (FGF9) is a potent mitogen that stimulates normal and cancer cell proliferation though the signaling mechanism is not fully understood. In this study, we aimed to unravel the signaling cascades mediate FGF9 actions in human uterine endometrial stromal cell. Our results demonstrate that the mitogenic effect of FGF9 is transduced via two parallel but additive signaling pathways involving mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase. Activation of mTOR by FGF9 induces p70 ribosomal S6 kinase (S6K1) phosphorylation, cyclin expression, and cell proliferation, which are independent of phosphatidylinositol 3-kinase and Akt. Coimmunoprecipitation analysis demonstrates that mTOR physically associates with S6K1 upon FGF9 treatment, whereas ablation of mTOR activity using RNA interference or pharmacological inhibitor blocks S6K1 phosphorylation and cell proliferation induced by FGF9. Further study demonstrates that activation of mTOR is regulated by a phospholipase C␥-controlled calcium signaling pathway. These studies provide evidence to demonstrate, for the first time, that a novel signaling cascade involving phospholipase C␥, calcium, mTOR, and S6K1 is activated by FGF9 in a receptor-specific manner.Fibroblast growth factor-9 (FGF9), 1 a potent mitogen and survival factor for numerous cell types (1-6), belongs to a heparin-binding polypeptide family that consists of at least 23 structurally related proteins (7,8). Expression of FGF9 plays critical roles in sex determination, bone formation, neuron development, lens fiber differentiation, and gap junction formation (4, 9 -12). Null-allele mice lacking FGF9 exhibit severe lung hypoplasia and die shortly after birth (4). On the other hand, aberrant expression of FGF9 is associated with the development of several human diseases including prostate cancer, brain tumor, and endometriosis (3, 6, 13). Despite its well studied biological functions, the signaling mechanism of FGF9 remains to be identified.The signaling of FGF is mediated via complex interactions between specific members of the FGF family and one or more FGF receptor isoforms. Receptors for FGF (FGFR1 to -4) are tyrosine kinase receptors consisting of two intracellular tyrosine kinase domains, a single transmembrane domain, and an extracellular portion that contains three immunoglobulin-like (Ig) domains. The third Ig domain (Ig III), which exerts the highest impact on FGF receptor binding specificity and tissuespecific expression patterns, is the region in which alternative splicing occurs. Three different splice variants (designated as IIIa, IIIb, and IIIc) have been identified for FGFR1 and FGFR2, whereas only the IIIb and IIIc variants have been detected for FGFR3 (14 -17). As of yet, no splice variant for FGFR4 has been identified. The splicing variant "IIIa" of FGFR is a secreted protein, whereas IIIb and IIIc are both membrane-bound receptors containing mutually exclusive Ig III domains. It is generally believed that the IIIb isoform of FGFRs is ex...

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Section: Discussioncontrasting

confidence: 45%

mentioning

confidence: 99%

The Mammalian Target of Rapamycin-p70 Ribosomal S6 Kinase but Not Phosphatidylinositol 3-Kinase-Akt Signaling Is Responsible for Fibroblast Growth Factor-9-induced Cell Proliferation

Wing

Chen

Chuang

et al. 2005

Journal of Biological Chemistry

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“…Stk40 Induces ESC Differentiation Through Activation of the Erk/ MAPK Pathway. Experimental evidence suggests that multiple signaling pathways including the Erk/MAPK, TGF-β, and PI3K pathways might be involved in ExEn development (4,(20)(21)(22). Using inhibitors of these pathways, we found that only the Mek1/ 2 inhibitor (U0126) abrogated Stk40-induced ESC differentiation, which was determined by both cell morphology and Sox7 expression (Fig.…”

Section: Forced Expression Of Stk40 Induces Esc Differentiation Into mentioning

confidence: 88%

Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation

Sun

Gao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Self-renewal and differentiation of embryonic stem cells (ESCs) are controlled by intracellular transcriptional factors and extracellular factor-activated signaling pathways. Transcription factor Oct4 is a key player maintaining ESCs in an undifferentiated state, whereas the Erk/MAPK pathway is known to be important for ESC differentiation. However, the manner in which intracellular pluripotency factors modulate extracellular factor-activated signaling pathways in ESCs is not well understood. Here, we report identification of a target gene of Oct4, serine/threonine kinase 40 (Stk40), which is able to activate the Erk/MAPK pathway and induce extraembryonicendoderm (ExEn) differentiation in mouse ESCs. Interestingly, cells overexpressing Stk40 exclusively contribute to the ExEn layer of chimeric embryos when injected into host blastocysts. In contrast, deletion of Stk40 in ESCs markedly reduces ExEn differentiation in vitro. Mechanistically, Stk40 interacts with Rcn2, which also activates Erk1/2 to induce ExEn specification in mouse ESCs. Moreover, Rcn2 proteins are specifically located in the cytoplasm of the ExEn layer of early mouse embryos. Importantly, knockdown of Rcn2 blocks Stk40-activated Erk1/2 and ESC differentiation. Therefore, our study establishes a link between the pluripotency factor Oct4 and the Erk/MAPK signaling pathway, and it uncovers cooperating signals in the Erk/ MAPK activation that control ExEn differentiation.embryonic stem cells | Rcn2 | Ras | Gata6

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“…Cumulative evidence on mESCs consistently revealed that the interaction between FGFs and their receptors led to the upregulation of ECM molecules through the activation of PI3K/Akt/PKB [27,28], and that this promoted basement …”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Contribution of the PI3K/Akt/PKB signal pathway to maintenance of self‐renewal in human embryonic stem cells

Kim

Cheon

Yoo³

et al. 2004

FEBS Letters

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Although basic fibroblast growth factor (FGF2) is generally included in the media for maintenance of human embryonic stem cells (hESCs), the action of FGF2 in these cells has not been well defined. Here, we determined the roles of FGF2 in maintaining hESC self-renewal. Withdrawal of FGF2 from the media led to acquisition of typical differentiated characteristics in hESCs. In the presence of FGF2, which is normally required for proliferation in an undifferentiated state, inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/PKB signal stimulated differentiation and attenuated the expression of extracellular matrix (ECM) molecules. We suggest that FGF2 maintains hESC self-renewal by supporting stable expression of ECM molecules through activation of the PI3K/Akt/PKB pathway.

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Fibroblast growth factor (FGF) signaling through PI 3-kinase and Akt/PKB is required for embryoid body differentiation

Cited by 120 publications

References 48 publications

The Mammalian Target of Rapamycin-p70 Ribosomal S6 Kinase but Not Phosphatidylinositol 3-Kinase-Akt Signaling Is Responsible for Fibroblast Growth Factor-9-induced Cell Proliferation

The Mammalian Target of Rapamycin-p70 Ribosomal S6 Kinase but Not Phosphatidylinositol 3-Kinase-Akt Signaling Is Responsible for Fibroblast Growth Factor-9-induced Cell Proliferation

Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation

RETRACTED: Contribution of the PI3K/Akt/PKB signal pathway to maintenance of self‐renewal in human embryonic stem cells

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