Src Inhibits the Hippo Tumor Suppressor Pathway through Tyrosine Phosphorylation of Lats1

Su, Yuan; Ji, Xinyan; Cao, Xiaolei; Dai, Xiaoming; Xu, Li; Zhao, Hongxia; Guo, Xiaohong; Yan, Huan; Zhang, Haitao; Zhu, Chengzhan; Zhou, Qi; Tang, Mei; Xia, Zongping; Li, Li; Cong, Yu‐Sheng; Ye, Sheng; Liang, Tingbo; Feng, Xin‐Hua; Zhao, Bin

doi:10.1158/0008-5472.can-17-0391

Cited by 123 publications

(133 citation statements)

References 52 publications

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“…Cell adhesion and cell contractility act via Src kinases to activate YAP by antagonizing LATS-mediated phosphorylation of YAP S127, a major target for Hippo signaling (Kim and Gumbiner 2015;Si et al 2017; for review, see Meng et al 2016). Cell adhesion, actomyosin contractility, and Src kinases are also required for maintenance of active YAP in CAFs (Calvo et al 2013).…”

Section: Mrtf-srf Signaling Activates Yap Through Cell Contractilitymentioning

confidence: 99%

Mutual dependence of the MRTF–SRF and YAP–TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics

2017

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Both the MRTF-SRF and the YAP-TEAD transcriptional regulatory networks respond to extracellular signals and mechanical stimuli. We show that the MRTF-SRF pathway is activated in cancer-associated fibroblasts (CAFs). The MRTFs are required in addition to the YAP pathway for CAF contractile and proinvasive properties. We compared MRTF-SRF and YAP-TEAD target gene sets and identified genes directly regulated by one pathway, the other, or both. Nevertheless, the two pathways exhibit mutual dependence. In CAFs, expression of direct MRTF-SRF genomic targets is also dependent on YAP-TEAD activity, and, conversely, YAP-TEAD target gene expression is also dependent on MRTF-SRF signaling. In normal fibroblasts, expression of activated MRTF derivatives activates YAP, while activated YAP derivatives activate MRTF. Cross-talk between the pathways requires recruitment of MRTF and YAP to DNA via their respective DNA-binding partners (SRF and TEAD) and is therefore indirect, arising as a consequence of activation of their target genes. In both CAFs and normal fibroblasts, we found that YAP-TEAD activity is sensitive to MRTF-SRF-induced contractility, while MRTF-SRF signaling responds to YAP-TEAD-dependent TGFβ signaling. Thus, the MRF-SRF and YAP-TEAD pathways interact indirectly through their ability to control cytoskeletal dynamics.

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Section: Mrtf-srf Signaling Activates Yap Through Cell Contractilitymentioning

confidence: 99%

Mutual dependence of the MRTF–SRF and YAP–TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics

2017

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“…The exact role of Src in this regulation is still under debate and different alternative pathways have been proposed. On the one hand, Src was shown to directly phosphorylate YAP or its upstream kinase LATS1/2 and thereby promotes YAP nuclear translocation [39,40]. One the other hand, Src is a well-known regulator of Rac-1 and this later protein was described being involved in YAP nuclear translocation as well [14,41].…”

Section: Discussionmentioning

confidence: 99%

Integrin-dependent YAP signaling requires LAMTOR1 mediated delivery of Src to the plasma membrane

Bouvard

Block

Brunner

et al. 2019

Preprint

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YAP signaling has emerged as an important signaling pathway involved in several normal and pathological processes. While main upstream effectors regulating its activity have been extensively studied, the interplay with other cellular processes has been far less analyzed. Here, we identified the LAMTOR complex as a new important regulator of YAP signaling. We uncovered that p18/LAMTOR1 is required for the recycling of Src on late endosomes to the cell periphery, and consequently to activate a signaling cascade that eventually controls YAP nuclear shuttling. Moreover, p18/LAMTOR1 positives late endosomes distribution is controlled by β1 integrins, extracellular matrix stiffness and cell contractility. This likely relies on the targeting of microtubules to β1 positive focal adhesion via ILK. Altogether our findings identify the late endosomal recycling pathway as a major regulator of YAP.3

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“…An alternative mechanism is also described for the FAK‐linked regulation of YAP, involving the dephosphorylation of Ser397 by the protein phosphatase PP1A (Hu et al, 2017). Src can also promote YAP activity by its direct phosphorylation in addition to phosphorylating and inactivating the LATS (P. Li et al, 2016; Si et al, 2017; Taniguchi et al, 2015). The other downstream effectors of integrin signaling, including JNK, Rho, and Ras are also linked to the regulation of YAP proteins (Meng, Moroishi, & Guan, 2016).…”

Section: The Molecular Cascade Involved In the Control Of Eb Formatiomentioning

confidence: 99%

The role of Hippo signaling pathway and mechanotransduction in tuning embryoid body formation and differentiation

Gueguen

Omidi

Ostadrahimi

et al. 2020

Journal Cellular Physiology

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Embryoid bodies (EBs) are the three‐dimensional aggregates of pluripotent stem cells that are used as a model system for the in vitro differentiation. EBs mimic the early stages of embryogenesis and are considered as a potential biomimetic body in tuning the stem cell fate. Although EBs have a spheroid shape, they are not formed accidentally by the agglomeration of cells; they are formed by the deliberate and programmed aggregation of stem cells in a complex topological and biophysical microstructure instead. EBs could be programmed to promisingly differentiate into the desired germ layers with specific cell lineages, in response to intra‐ and extra‐biochemical and biomechanical signals. Hippo signaling and mechanotransduction are the key pathways in controlling the formation and differentiation of EBs. The activity of the Hippo pathway strongly relies on cell–cell junctions, cell polarity, cellular architecture, cellular metabolism, and mechanical cues in the surrounding microenvironment. Although the Hippo pathway was initially thought to limit the size of the organ by inhibiting the proliferation and the promotion of apoptosis, the evidence suggests that this pathway even regulates stem cell self‐renewal and differentiation. Considering the abovementioned explanations, the present study investigated the interplay of the Hippo signaling pathway, mechanotransduction, differentiation, and proliferation pathways to draw the molecular network involved in the control of EBs fate. In addition, this study highlighted several neglected critical parameters regarding EB formation, in the interplay with the Hippo core component involved in the promising differentiation.

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Src Inhibits the Hippo Tumor Suppressor Pathway through Tyrosine Phosphorylation of Lats1

Cited by 123 publications

References 52 publications

Mutual dependence of the MRTF–SRF and YAP–TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics

Mutual dependence of the MRTF–SRF and YAP–TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics

Integrin-dependent YAP signaling requires LAMTOR1 mediated delivery of Src to the plasma membrane

The role of Hippo signaling pathway and mechanotransduction in tuning embryoid body formation and differentiation

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