Src Family Kinase Activity Is Required for Murine Embryonic Stem Cell Growth and Differentiation

Meyn, Malcolm A.; Schreiner, Steven J.; Dumitrescu, Teodora Pene; Nau, Gerard J.; Smithgall, Thomas E.

doi:10.1124/mol.104.010231

Cited by 74 publications

(127 citation statements)

References 42 publications

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…Because all these processes are involved in embryogenesis, it is not surprising that seven SFKs have so far been identified to be expressed in ES cells and at least three of these, Yes, Hck and Lck, undergo dynamic changes in transcriptional and post-transcriptional regulation during human and mouse ES cell differentiation and are activated by LIF (Annerén et al, 2004;Ernst et al, 1994;Meyn et al, 2005). Interestingly, it was recently proposed that individual SFKs control distinct and opposing pathways in ES cell with Yes, Hck and Lck supporting self-renewal, whereas Src, which remains highly expressed in ES cells during differentiation, promotes differentiation into primitive ectoderm (Meyn et al, 2005;Meyn and Smithgall, 2009).…”

Section: Introductionmentioning

confidence: 99%

Regulation of mouse embryonic stem cell self-renewal by a Yes–YAP–TEAD2 signaling pathway downstream of LIF

Tamm¹,

Böwer²,

Annerén³

2011

Development

View full text Add to dashboard Cite

SummaryThe cytoplasmic tyrosine kinase Yes has previously been shown to have an important role in maintaining mouse and human embryonic stem (ES) self-renewal through an unknown pathway downstream of leukemia inhibitory factor (LIF) and one or more factors in serum. Here, we show that TEAD2 and its transcriptional co-activator, the Yes-associated protein YAP, co-operate in a signaling pathway downstream of Yes. We show that YAP, TEAD2 and Yes are highly expressed in self-renewing ES cells, are activated by LIF and serum, and are downregulated when cells are induced to differentiate. We also demonstrate that kinase-active Yes binds and phosphorylates YAP, and activates YAP-TEAD2-dependent transcription. We found that TEAD2 associates directly with the Oct-3/4 promoter. Moreover, activation of the Yes pathway induced activity of the Oct-3/4 and Nanog promoters, whereas suppression of this pathway inhibited promoter activity. Nanog, in turn, suppressed TEAD2-dependent promoter activity, whereas siRNA-mediated knockdown of Nanog induced it, suggesting a negative regulatory feedback loop. Episomal supertransfection of cells with inhibitory TEAD2-EnR induced endodermal differentiation, which suggests that this pathway is necessary for ES cell maintenance.

show abstract

Section: Introductionmentioning

confidence: 99%

Regulation of mouse embryonic stem cell self-renewal by a Yes–YAP–TEAD2 signaling pathway downstream of LIF

Tamm¹,

Böwer²,

Annerén³

2011

Development

View full text Add to dashboard Cite

show abstract

“…In summary, the article by Meyn et al (2005) supports the ideas that individual members of the Src kinase family control discrete aspects of stem cell behavior and that individual SFKs represent targets for the manipulation of stem cell fate with small molecule inhibitors in culture. The conserved structural architecture of SFK domains may make the design of isoform-selective inhibitors difficult (Boggon and Eck, 2004), but we know from experience with inhibitors of other protein tyrosine kinases, such as the Brc-Abl inhibitor imatinib, that specificity can be achieved (Capdeville et al, 2002).…”

Section: -895xmentioning

confidence: 58%

“…It is interesting that analysis of SKI-1 IC 50 values against purified SFKs in vitro reveal this inhibitor to be more active against the putative "self-renewal" kinases Hck and Yes than against Fyn and Src, which remain active as ES cells differentiate to embryoid bodies. The implication is that the activity of Src and Fyn are essential for embryoid body formation.In summary, the article by Meyn et al (2005) supports the ideas that individual members of the Src kinase family control discrete aspects of stem cell behavior and that individual SFKs represent targets for the manipulation of stem cell fate with small molecule inhibitors in culture. The conserved structural architecture of SFK domains may make the design of isoform-selective inhibitors difficult (Boggon and Eck, 2004), but we know from experience with inhibitors of other protein tyrosine kinases, such as the Brc-Abl inhibitor imatinib, that specificity can be achieved (Capdeville et al, 2002).…”

mentioning

confidence: 58%

Live Long and Prosper: Fig. 1.

Lazo

2005

Mol Pharmacol

View full text Add to dashboard Cite

In this issue of Molecular Pharmacology, Meyn et al. (p. 1320) provide the results of the first comprehensive investigation of the expression pattern of the Src family of nonreceptor tyrosine kinases (SFK) in mouse embryonic stem (ES) cells. They found that self-renewing ES cells express seven of the eight mammalian SFK members and that some undergo distinct expression changes during early differentiation events. One of the most dramatic changes was in Hck transcript levels, which decreased almost 30-fold during the first 3 days of embryoid body formation, a culture system model of early embryogenesis and differentiation. Other SFKs, such as Fyn and Src, remain present and active as ES cells differentiate. Of particular interest was the observation that ES cell self-renewal or differentiation can be manipulated through the selective pharmacological inhibition of SFK members. This information should help in the expanding efforts to exploit ES cells for basic and clinical purposes.We all begin modestly when our father's sperm meets our mother's egg. To live long and prosper, we must employ unspecialized precursor cells or stem cells, which have the unique ability to self-renew and differentiate into specialized cells in response to appropriate signals. These stem cells are categorized as either embryonic or tissue-specific; embryonic stem (ES) cells are derived from the inner cell mass of the early embryo (blastocyst) and tissue-specific stem cells (adult stem cells) are unspecialized cells found in differentiated tissues. ES cells can give rise to any differentiated cell type derived from the three primary germ layers of the embryo (endoderm, mesoderm, and ectoderm), as well as germ cells. Because of this remarkable developmental potential, ES cells hold substantial therapeutic promise for transplantation and regenerative medicine (Keller, 2005).ES cells generally can be maintained in culture in an undifferentiated state indefinitely without losing differentiation potential. When injected into a host, they will produce a benign teratoma containing multiple tissue types. Therefore, it is likely that ES cells will need to be differentiated into the desired tissue and subtype-specific cells before they can be used clinically. Seeking methods to maintain "stemness", while permitting expansion of the cells and guiding their differentiation along a desired lineage before transplant, has been a major challenge. Most investigators have used 'cocktails' of growth factors, signaling molecules, or genetic manipulation (Keller, 2005;Wobus and Boheler, 2005), but others have recently begun to use small organic molecules to influence stem cell behavior (Ding and Schultz, 2004). As we start to understand the central signaling pathways controlling ES cell self-renewal and differentiation, it should be possible to identify rational molecular targets for small molecule intervention. In the current issue, Meyn at al. (2005) have performed the first systematic analysis of the Src family of protein-tyrosine kinases (SFKs) i...

show abstract

“…A requirement for Src family kinases in the formation of primitive ectoderm from ES cells was shown by the ability of broad specificity inhibitors to prevent ES cell differentiation on LIF withdrawal [168]. Using an elegant chemical genetics approach the formation of primitive ectoderm from ES cells in culture was shown to require signalling through cSRC and that inhibiting this transition effectively inhibited further differentiation [167].…”

Section: Mechanisms That Regulate Pluripotent Cell Progression: What mentioning

confidence: 99%

“…Alternative formulations of inhibitor medium have been developed by others, substituting ERK inhibition by inhibition of SRC kinases or inhibition of calcineurin signalling [165,166]. SRC kinase has been shown to be required for the differentiation of ES cells to primitive ectoderm [167,168]. ERK inhibitors, SRC kinase inhibitors, and inhibition of calcineurin signalling, therefore, share a common function and prevent differentiation within the context of inhibitor-based medium formulations; this is likely through the prevention of cSRC activation, a process mediated by calcineurin-NFAT and ERK1/2 [166].…”

Section: Stat3mentioning

confidence: 99%

The States of Pluripotency: Pluripotent Lineage Development in the Embryo and in the Dish

Rathjen

2014

ISRN Stem Cells

View full text Add to dashboard Cite

The pluripotent cell lineage of the embryo comprises a series of temporally and functionally distinct intermediary cell states, the epiblast precursor cell of the newly formed blastocyst, the epiblast population of the inner cell mass, and the early and late epiblast of the postimplantation embryo, referred to here as early and late primitive ectoderm. Pluripotent cell populations representative of the embryonic populations can be formed in culture. Although multiple pluripotent cell states are now recognised, little is known about the signals and pathways that progress cells from the epiblast precursor cell to the late primitive ectoderm in the embryo or in culture. The characterisation of cell states is most advanced in mouse where conditions for culturing distinct pluripotent cell states are well established and embryonic material is accessible. This review will focus on the pluripotent cell states present during embryonic development in the mouse and what is known of the mechanisms that regulate the progression of the lineage from the epiblast precursor cell and the ground state of pluripotency to the late primitive ectoderm present immediately prior to cell differentiation.

show abstract

Src Family Kinase Activity Is Required for Murine Embryonic Stem Cell Growth and Differentiation

Cited by 74 publications

References 42 publications

Regulation of mouse embryonic stem cell self-renewal by a Yes–YAP–TEAD2 signaling pathway downstream of LIF

Regulation of mouse embryonic stem cell self-renewal by a Yes–YAP–TEAD2 signaling pathway downstream of LIF

Live Long and Prosper: Fig. 1.

The States of Pluripotency: Pluripotent Lineage Development in the Embryo and in the Dish

Contact Info

Product

Resources

About