MT1-MMP-Dependent Control of Skeletal Stem Cell Commitment via a β1-Integrin/YAP/TAZ Signaling Axis

Tang, Yi; Rowe, R. Grant; Botvinick, Elliot L.; Kurup, Abhishek; Putnam, Andrew J.; Seiki, Motoharu; Weaver, Valerie M.; Keller, Evan T.; Goldstein, Steven A.; Dai, Jinlu; Begun, Dana L.; Saunders, Thomas L.; Weiss, Stephen J.

doi:10.1016/j.devcel.2013.04.011

Cited by 234 publications

(278 citation statements)

References 64 publications

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“…Our data indicate that endothelial cell interaction with the RGDKGE epitope was associated with enhanced nuclear accumulation of YAP. Integrin signaling may play a role in the regulation of YAP as studies have implicated a role for ␤1-integrins expressed in skeletal stem cells and ␣V-integrins expressed in osteoblasts in governing YAP subcellular localization (69,70). Our findings are consistent with a mechanism by which ␣v␤3-mediated binding to the RGDKGE epitope, but not the related RGDAPG epitope, stimulates a signaling cascade leading to enhanced nuclear accumulation of YAP that depends on Src and/or p38 MAPK.…”

Section: Discussionsupporting

confidence: 86%

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Ames

Contois

Caron

et al. 2016

Journal of Biological Chemistry

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Extracellular matrix (ECM) remodeling regulates angiogenesis. However, the precise mechanisms by which structural changes in ECM proteins contribute to angiogenesis are not fully understood. Integrins are molecules with the ability to detect compositional and structural changes within the ECM and integrate this information into a network of signaling circuits that coordinate context-dependent cell behavior. The role of integrin ␣v␤3 in angiogenesis is complex, as evidence exists for both positive and negative functions. The precise downstream signaling events initiated by ␣v␤3 may depend on the molecular characteristics of its ligands. Here, we identified an RGD-containing cryptic collagen epitope that is generated in vivo. Surprisingly, rather than inhibiting ␣v␤3 signaling, this collagen epitope promoted ␣v␤3 activation and stimulated angiogenesis and inflammation. An antibody directed to this RGDKGE epitope but not other RGD collagen epitopes inhibited angiogenesis and inflammation in vivo. The selective ability of this RGD epitope to promote angiogenesis and inflammation depends in part on its flanking KGE motif. Interestingly, a subset of macrophages may represent a physiologically relevant source of this collagen epitope. Here, we define an endothelial cell mechano-signaling pathway in which a cryptic collagen epitope activates ␣v␤3 leading to an Src and p38 MAPK-dependent cascade that leads to nuclear accumulation of Yes-associated protein (YAP) and stimulation of endothelial cell growth. Collectively, our findings not only provide evidence for a novel mechano-signaling pathway, but also define a possible therapeutic strategy to control ␣v␤3 signaling by targeting a proangiogenic and inflammatory ligand of ␣v␤3 rather than the receptor itself.

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Section: Discussionsupporting

confidence: 86%

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Ames

Contois

Caron

et al. 2016

Journal of Biological Chemistry

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“…2D) (Haslam et al, 2008;Simian et al, 2001). Consistent with the premise that MMPs are able to drive type I collagen-invasive activity (Alcaraz et al, 2011;Chun et al, 2004;Mori et al, 2009Mori et al, , 2013Sabeh et al, 2009;Simian et al, 2001;Tang et al, 2013;Weaver et al, 2014), branching morphogenesis is inhibited completely when organoids are cultured in the presence of the pan-specific MMP inhibitor BB-94 (Chun et al, 2004;Sabeh et al, 2009) (Fig. 2E).…”

Section: Mmp14-dependent Regulation Of Branching Morphogenesis: In VIsupporting

confidence: 87%

Functional roles of MMP14 and MMP15 in early postnatal mammary gland development

et al. 2016

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During late embryogenesis, mammary epithelial cells initiate migration programs that drive ductal invasion into the surrounding adipose-rich mesenchyme. Currently, branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases MMP14 (MT1-MMP) and MMP15 (MT2-MMP), which drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remain undefined. Here, we characterize the impact of global Mmp14 and Mmp15 targeting on early postnatal mammary gland development in mice. Unexpectedly, both Mmp14 −/− and Mmp15 −/− mammary glands retain the ability to generate intact ductal networks. Although neither proteinase is required for branching morphogenesis, transcriptome profiling reveals a key role for MMP14 and MMP15 in regulating mammary gland adipocyte differentiation. Whereas MMP14 promotes the generation of white fat depots crucial for energy storage, MMP15 differentially controls the formation of thermogenic brown fat. Taken together, these data not only indicate that current paradigms relevant to proteinase-dependent morphogenesis need be revisited, but also identify new roles for the enzymes in regulating adipocyte fate determination in the developing mammary gland.

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“…Thus, the recent observations indicating that TAZ/YAP localization is influenced by mechanical cues provide a molecular explanation for how cytoskeletal dynamics are integrated with cell fate. Although the regulation of TAZ/ YAP localization by mechanical stimuli is still poorly understood, recent work indicates that an MT1-MMP/β1-integrin/Rho-GTPase signaling cascade is involved, as activation of these signals promotes skeletal stem cell commitment in a TAZ/YAP-dependent manner (Tang et al, 2013). Intriguingly, recent work suggests that the regulation of TAZ and YAP localization by mechanical cues is independent of the LATS1/2 kinases.…”

Section: Mechanical Cues and Gpcrs: Novel Upstream Regulators Of Taz/yapmentioning

confidence: 99%

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

2014

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Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.

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MT1-MMP-Dependent Control of Skeletal Stem Cell Commitment via a β1-Integrin/YAP/TAZ Signaling Axis

Cited by 234 publications

References 64 publications

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

Functional roles of MMP14 and MMP15 in early postnatal mammary gland development

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

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