Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs

Kastan, Nathaniel; Oak, Sanyukta; Liang, Rui; Baxt, Leigh A.; Myers, Robert W.; Ginn, John D.; Liverton, Nigel J.; Huggins, David J.; Pichardo, John; Paul, Matthew R.; Carroll, Thomas; Nagiel, Aaron; Gnedeva, Ksenia; Hudspeth, A. J.

doi:10.1073/pnas.2206113119

Cited by 12 publications

(7 citation statements)

References 26 publications

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“…YAP/TAZ reactivation assay was performed using the YAP/TAZ activator TRULI 36 . Ad‐ Csrp2‐infected ASMCs were seeded in a 6‐well plate a density of 1 × 10 5 cells/well.…”

Section: Methodsmentioning

confidence: 99%

“…YAP/TAZ reactivation assay was performed using the YAP/TAZ activator TRULI. 36 Ad-Csrp2-infected ASMCs were seeded in a 6well plate a density of 1 × 10 5 cells/well. After overnight culture, the cells were treated with 10 µM of TRULI (Selleck, Shanghai, China) for 24 h. YAP/TAZ deactivation assay was performed using the YAP/TAZ inhibitor-1.…”

Section: Yap/taz Reactivation or Deactivation Experimentsmentioning

confidence: 99%

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Cysteine and glycine‐rich protein 2 retards platelet‐derived growth factor‐BB‐evoked phenotypic transition of airway smooth muscle cells by decreasing YAP/TAZ activity

Wang,

Zhang,

Zhong

et al. 2023

Cell Biochemistry & Function

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Cysteine and glycine‐rich protein 2 (Csrp2) has emerged as a key factor in controlling the phenotypic modulation of smooth muscle cells. The phenotypic transition of airway smooth muscle cells (ASMCs) is a pivotal step in developing airway remodeling during the onset of asthma. However, whether Csrp2 mediates the phenotypic transition of ASMCs in airway remodeling during asthma onset is undetermined. This work aimed to address the link between Csrp2 and the phenotypic transition of ASMCs evoked by platelet‐derived growth factor (PDGF)‐BB in vitro. The overexpression or silencing of Csrp2 in ASMCs was achieved through adenovirus‐mediated gene transfer. The expression of mRNA was measured by quantitative real‐time‑PCR. Protein levels were determined through Western blot analysis. Cell proliferation was detected by EdU assay and Calcein AM assays. Cell cycle distribution was assessed via fluorescence‐activated cell sorting assay. Cell migration was evaluated using the scratch‐wound assay. The transcriptional activity of Yes‐associated protein (YAP)/transcriptional coactivator with PDZ‐binding motif (TAZ) was measured using the luciferase reporter assay. A decline in Csrp2 level occurred in PDGF‐BB‐stimulated ASMCs. Increasing Csrp2 expression repressed the PDGF‐BB‐evoked proliferation and migration of ASMCs. Moreover, increasing Csrp2 expression impeded the phenotypic change of PDGF‐BB‐stimulated ASMCs from a contractile phenotype into a synthetic/proliferative phenotype. On the contrary, the opposite effects were observed in Csrp2‐silenced ASMCs. The activity of YAP/TAZ was elevated in PDGF‐BB‐stimulated ASMCs, which was weakened by Csrp2 overexpression or enhanced by Csrp2 silencing. The YAP/TAZ activator could reverse Csrp2‐overexpression‐mediated suppression of the PDGF‐BB‐evoked phenotypic switching of ASMCs, while the YAP/TAZ suppressor could dimmish Csrp2‐silencing‐mediated enhancement on PDGF‐BB‐evoked phenotypic switching of ASMCs. In summary, Csrp2 serves as a determinant for the phenotypic switching of ASMCs. Increasing Csrp2 is able to impede PDGF‐BB‐evoked phenotypic change of ASMCs from a synthetic phenotype into a synthetic/proliferative phenotype through the effects on YAP/TAZ. This work implies that Csrp2 may be a key player in airway remodeling during the onset of asthma.

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“…YAP/TAZ reactivation assay was performed using the YAP/TAZ activator TRULI 36 . Ad‐ Csrp2‐infected ASMCs were seeded in a 6‐well plate a density of 1 × 10 5 cells/well.…”

Section: Methodsmentioning

confidence: 99%

Section: Yap/taz Reactivation or Deactivation Experimentsmentioning

confidence: 99%

Cysteine and glycine‐rich protein 2 retards platelet‐derived growth factor‐BB‐evoked phenotypic transition of airway smooth muscle cells by decreasing YAP/TAZ activity

Wang,

Zhang,

Zhong

et al. 2023

Cell Biochemistry & Function

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“…Gain or loss of YAP function modulates the expression of genes that regulate cell proliferation and survival (diap1, bantam, cyclin E, and E2F1), the Hippo pathway (Kibra, Crb, and Fj), and cell-cell interaction (E-Cadherin, Serrate, Wingless, and Vein) (Pan 2010). The role of YAP in the regulation of ocular tissue development and function has been extensively studied (Kastan et al 2022;Lu et al 2020). Indeed, YAP has been shown to be expressed in the RPE and the ciliary margin of the optic cup as well as corneal epithelial and lens epithelial cells, iris, and retina where it localized in the inner nuclear layer (Hamon et al 2019(Hamon et al , 2017.…”

Section: Yap Signaling In Retinal Neurogenesis and Gliogenesismentioning

confidence: 99%

CCN–Hippo YAP signaling in vision and its role in neuronal, glial and vascular cell function and behavior

Chaqour

2023

J. Cell Commun. Signal.

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The retina is a highly specialized tissue composed of a network of neurons, glia, and vascular and epithelial cells; all working together to coordinate and transduce visual signals to the brain. The retinal extracellular matrix (ECM) shapes the structural environment in the retina but also supplies resident cells with proper chemical and mechanical signals to regulate cell function and behavior and maintain tissue homeostasis. As such, the ECM affects virtually all aspects of retina development, function and pathology. ECM‐derived regulatory cues influence intracellular signaling and cell function. Reversibly, changes in intracellular signaling programs result in alteration of the ECM and downstream ECM‐mediated signaling network. Our functional studies in vitro, genetic studies in mice, and multi omics analyses have provided evidence that a subset of ECM proteins referred to as cellular communication network (CCN) affects several aspects of retinal neuronal and vascular development and function. Retinal progenitor, glia and vascular cells are major sources of CCN proteins particularly CCN1 and CCN2. We found that expression of the CCN1 and CCN2 genes is dependent on the activity of YAP, the core component of the hippo‐YAP signaling pathway. Central to the Hippo pathway is a conserved cascade of inhibitory kinases that regulate the activity of YAP, the final transducer of this pathway. Reversibly, YAP expression and/or activity is dependent on CCN1 and CCN2 downstream signaling, which creates a positive or negative feedforward loop driving developmental processes (e.g., neurogenesis, gliogenesis, angiogenesis, barriergenesis) and, when dysregulated, disease progression in a range of retinal neurovascular disorders. Here we describe mechanistic hints involving the CCN–Hippo–YAP regulatory axis in retina development and function. This regulatory pathway represents an opportunity for targeted therapies in neurovascular and neurodegenerative diseases.

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“…For instance, MST inhibitors such as compound 51 and XMU-XP-1 failed to activate hiPSC-CM proliferation due to off-target effects on many pivotal cell cycle genes [ 29 ]. Recently, Kastan and colleagues have chemically modified a LATS inhibitor, TRULI [ 34 ]. Its derivative, TDI-011536, showed improved potency and physical-chemical properties and initiated the proliferation of CMs in adult mice following cardiac cryolesions, suggesting that drug modification might provide more possibilities for improving the effects of pro-proliferative compounds [ 34 ].…”

Section: Regulators Of Hipsc-cm Proliferation and Maturationmentioning

confidence: 99%

Recent advances in regulating the proliferation or maturation of human-induced pluripotent stem cell-derived cardiomyocytes

Yang,

Kiskin

et al. 2023

Stem Cell Res Ther

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In the last decade, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM)-based cell therapy has drawn broad attention as a potential therapy for treating injured hearts. However, mass production of hiPSC-CMs remains challenging, limiting their translational potential in regenerative medicine. Therefore, multiple strategies including cell cycle regulators, small molecules, co-culture systems, and epigenetic modifiers have been used to improve the proliferation of hiPSC-CMs. On the other hand, the immaturity of these proliferative hiPSC-CMs could lead to lethal arrhythmias due to their limited ability to functionally couple with resident cardiomyocytes. To achieve functional maturity, numerous methods such as prolonged culture, biochemical or biophysical stimulation, in vivo transplantation, and 3D culture approaches have been employed. In this review, we summarize recent approaches used to promote hiPSC-CM proliferation, and thoroughly review recent advances in promoting hiPSC-CM maturation, which will serve as the foundation for large-scale production of mature hiPSC-CMs for future clinical applications.

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Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs

Cited by 12 publications

References 26 publications

Cysteine and glycine‐rich protein 2 retards platelet‐derived growth factor‐BB‐evoked phenotypic transition of airway smooth muscle cells by decreasing YAP/TAZ activity

Cysteine and glycine‐rich protein 2 retards platelet‐derived growth factor‐BB‐evoked phenotypic transition of airway smooth muscle cells by decreasing YAP/TAZ activity

CCN–Hippo YAP signaling in vision and its role in neuronal, glial and vascular cell function and behavior

Recent advances in regulating the proliferation or maturation of human-induced pluripotent stem cell-derived cardiomyocytes

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