Pan‐Src Family Kinase Inhibitors Replace Sox2 during the Direct Reprogramming of Somatic Cells

Staerk, Judith; Lyssiotis, Costas A.; Medeiro, Lea A.; Bollong, Michael J.; Foreman, Ruth K.; Zhu, Shoutian; Garcia, Michael; Gao, Qing; Bouchez, Laure C.; Lairson, Luke L.; Charette, Bradley D.; Supeková, Lubica; Janes, Jeffrey; Brinker, Achim; Cho, Charles Y.; Jaenisch, Rudolf; Schultz, Peter G.

doi:10.1002/ange.201101042

Cited by 13 publications

(16 citation statements)

References 19 publications

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“…Finally, our results provide a strong rationale for the development of selective compounds to control c-Src vs. c-Yes activity; such compounds may allow more precise pharmacological manipulation of ES cell renewal and differentiation. Indeed, a recent unbiased chemical library screen identified broad-spectrum Src-family kinase inhibitors as potent enhancers of somatic cell reprogramming to an ES cell-like state (iPS cells) 28 . Our work predicts that a Src-selective inhibitor (or a c-Yes agonist) may provide an even greater enhancement in reprogramming efficiency.…”

Section: Discussionmentioning

confidence: 99%

c-Yes Tyrosine Kinase Is a Potent Suppressor of ES Cell Differentiation and Antagonizes the Actions of Its Closest Phylogenetic Relative, c-Src

2013

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ES cells are derived from the inner cell mass of the blastocyst stage embryo and are characterized by self-renewal and pluripotency. Previous work has shown that Src-family tyrosine kinases display dynamic expression and activity changes during ES cell differentiation, suggesting distinct functions in the control of developmental fate. Here we used ES cells to test the hypothesis that c-Src and its closest phylogenetic relative, c-Yes, act in biological opposition despite their strong homology. Unlike c-Src, enforced expression of active c-Yes blocked ES cell differentiation to embryoid bodies by maintaining pluripotency gene expression. To explore the interplay of c-Src and c-Yes in ES cell differentiation, we engineered c-Src and c-Yes mutants that are resistant to A-419259, a potent pyrrolopyrimidine inhibitor of the Src kinase family. Previous studies have shown that A-419259 treatment blocks all Src-family kinase activity in ES cells, preventing differentiation while maintaining pluripotency. Expression of inhibitor-resistant c-Src but not c-Yes rescued the A-419259 differentiation block, resulting in a cell population with properties of both primitive ectoderm and endoderm. Remarkably, when inhibitor-resistant c-Src and c-Yes were expressed together in ES cells, c-Yes activity suppressed c-Src mediated differentiation. These studies show that even closely related kinases such as c-Src and c-Yes have unique and opposing functions in the same cell type. Selective agonists or inhibitors of c-Src vs. c-Yes activity may allow more precise pharmacological manipulation of ES cell fate and have broader applications in other biological systems which express multiple Src family members such as tumor cells.

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Section: Discussionmentioning

confidence: 99%

c-Yes Tyrosine Kinase Is a Potent Suppressor of ES Cell Differentiation and Antagonizes the Actions of Its Closest Phylogenetic Relative, c-Src

2013

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“…While we incorporate numerous insights from cultured SCs throughout this review, we consider only genes whose genetic requirement for pluripotency has been demonstrated in the early embryo to be eligible for core PGN status. Also in contrast to the RDGN, for which the ability to induce ectopic retinal tissue provides a stringent test of sufficiency that defines a manageable number of candidate regulators, studies of mammalian cell pluripotency have produced an extensive literature on the reprogramming of somatic cells by application of small molecule cocktails, signaling pathway inhibitors, expression of miRNAs, co-expression of competing lineage specifiers, or substitution of PGN proteins with downstream targets (Anokye-Danso et al, 2011; Buganim et al, 2012; Chen et al, 2011; Ichida et al, 2009; Li et al, 2011; Lyssiotis et al, 2009; Miyoshi et al, 2011; Montserrat et al, 2013; Moon et al, 2011; Redmer et al, 2011; Shu et al, 2013; Staerk et al, 2011). Because most of these strategies are unlikely to regulate pluripotency in the early embryo, we limited our analysis to transcription factors or cofactors that can induce pluripotency on their own or in combination with other transcriptional proteins: Oct4, Nanog, Sox2, Sall4, Estrogen-related receptor beta (Esrrb), Kruppel-like factor 4 (Klf4), Nuclear receptor subfamily 5 group A member 2 (Nr5a2), Geminin (Gmnn), c-Myc and GATA-binding protein 3 (Gata3) (Feng et al, 2009; Festuccia et al, 2012; Heng et al, 2010; Kim et al, 2009a, 2009b; Li et al, 2011; Montserrat et al, 2013; Shu et al, 2015, 2013; Silva et al, 2009; Stuart et al, 2014; Takahashi et al, 2007; Takahashi and Yamanaka, 2006; Thorold W Theunissen et al, 2011; Tsai et al, 2011; Tsubooka et al, 2009; Yu et al, 2007; Zhu et al, 2010).…”

Section: Defining the Members Of Master Regulatory Networkmentioning

confidence: 99%

Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks

Davis

Rebay

2017

Developmental Biology

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Among the mechanisms that steer cells to their correct fate during normal development, master regulatory networks are unique in their sufficiency to trigger a developmental program outside of its normal context. In this review we discuss the key features that underlie master regulatory potency during normal and ectopic development, focusing on two examples, the retinal determination gene network (RDGN) that directs eye development in the fruit fly and the pluripotency gene network (PGN) that maintains cell fate competency in the early mammalian embryo. In addition to the hierarchical transcriptional activation, extensive positive transcriptional feedback, and cooperative protein-protein interactions that enable master regulators to override competing cellular programs, recent evidence suggests that network topology must also be dynamic, with extensive rewiring of the interactions and feedback loops required to navigate the correct sequence of developmental transitions to reach a final fate. By synthesizing the in vivo evidence provided by the RDGN with the extensive mechanistic insight gleaned from the PGN, we highlight the unique regulatory capabilities that continual reorganization into new hierarchies confers on master control networks. We suggest that deeper understanding of such dynamics should be a priority, as accurate spatiotemporal remodeling of network topology will undoubtedly be essential for successful stem cell based therapeutic efforts.

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“…More recently, another TGFβ receptor inhibitor, A-83-01, combined with a protein arginine methyltransferase inhibitor, AMI-5, enabled the reprogramming of mouse fibroblasts transduced with Oct4 alone (Yuan et al, 2011). Additional signaling pathway modulators, including a cAMP pathway activator, 8-bromoadenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) (17 in Figure 2), and inhibitors of Src family kinases were shown to induce and promote reprogramming as well (Staerk et al, 2011; Wang and Adjaye, 2011). …”

Section: Small Molecules That Modulate Reprogrammingmentioning

confidence: 99%

Chemical Approaches to Stem Cell Biology and Therapeutics

et al. 2013

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SUMMARY Small molecules that modulate stem cell fate and function offer significant opportunities that will allow the full realization of the therapeutic potential of stem cells. Rational design and screening for small molecules have identified useful compounds to probe fundamental mechanisms of stem cell self-renewal, differentiation, and reprogramming, and have facilitated the development of cell-based therapies and therapeutic drugs targeting endogenous stem and progenitor cells for repair and regeneration. Here, we will discuss recent scientific and therapeutic progress, as well as new perspectives and future challenges for using chemical approaches in stem cell biology and regenerative medicine.

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Pan‐Src Family Kinase Inhibitors Replace Sox2 during the Direct Reprogramming of Somatic Cells

Cited by 13 publications

References 19 publications

c-Yes Tyrosine Kinase Is a Potent Suppressor of ES Cell Differentiation and Antagonizes the Actions of Its Closest Phylogenetic Relative, c-Src

c-Yes Tyrosine Kinase Is a Potent Suppressor of ES Cell Differentiation and Antagonizes the Actions of Its Closest Phylogenetic Relative, c-Src

Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks

Chemical Approaches to Stem Cell Biology and Therapeutics

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