Talin1 Regulates Integrin Turnover To Promote Embryonic Epithelial Morphogenesis

Liu, Jie; He, Xiaowen; Qi, Yanmei; Tian, Xiaoxiang; Monkley, Susan J.; Critchley, David R.; Corbett, Siobhan; Lowry, Stephen F.; Graham, Alan M.; Li, Shaohua

doi:10.1128/mcb.01403-10

Cited by 37 publications

(39 citation statements)

References 49 publications

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“…Support for this hypothesis comes from our previous studies (17) where we showed that deletion of the Tln1 gene in CMs led to increased levels of β1D integrin. Likewise, work in other cell types has shown that Tln controls β1-integrin expression at the cell membrane (38,39).…”

Section: Discussionmentioning

confidence: 99%

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Manso

Okada

Sakamoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Continuous contraction-relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the musclespecific β1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. β1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper β1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.T he heart and all of its attendant cells, particularly the contracting cardiac myocytes (CMs), are constantly subjected to high forces. Proper linkage between the cellular cytoskeleton, the cell membrane (termed the sarcolemma in muscle cells), and the extracellular matrix (ECM) is necessary for synchronized force distribution among the cells of the myocardium (1-3). When these linkages are disturbed, forces may be distributed abnormally, cardiac muscle can be injured, and therefore whole-heart function can become abnormal. A number of intracellular proteins and membrane receptors have been found to be crucial for organizing this interactive arrangement between the intracellular CM environment and the surrounding ECM. The integrin family of adhesion receptors are key proteins operative in this response (4). Integrins are a large family of 18 α-subunits and 8 β-subunits, which heterodimerize noncovalently, forming over 24 unique transmembrane receptors on virtually all cells, including CMs. They bind directly to ECM proteins via their proportionally large extracellular domains, and their short cytoplasmic tails assist with organizing a large multiprotein complex that connects integrins to the actin cytoskeleton and may transduce signals to a range of downstream pathways. With these connections, integrins are recognized as key mechanotransducers, converting mechanical perturbations to biochemical signals (...

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Section: Discussionmentioning

confidence: 99%

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Manso

Okada

Sakamoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…18S RNA was used as a loading control as described previously. 47 Statistical analysis. Statistical analysis was performed using SigmaStat software (Systat Software, San Jose, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation during epithelial lumen formation

Liu

Saadat

et al. 2014

Cell Death Differ

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The tumor suppressor phosphatase and tensin homolog (PTEN) dephosphorylates PIP3 and antagonizes the prosurvival PI3K-Akt pathway. Targeted deletion of PTEN in mice led to early embryonic lethality. To elucidate its role in embryonic epithelial morphogenesis and the underlying mechanisms, we used embryonic stem cell-derived embryoid body (EB), an epithelial cyst structurally similar to the periimplantation embryo. PTEN is upregulated during EB morphogenesis in parallel with apoptosis of core cells, which mediates EB cavitation. Genetic ablation of PTEN causes Akt overactivation, apoptosis resistance and cavitation blockade. However, rescue experiments using mutant PTEN and pharmacological inhibition of Akt suggest that the phosphatase activity of PTEN and Akt are not involved in apoptosis-mediated cavitation. Instead, hypoxia-induced upregulation of Bnip3, a proapoptotic BH3-only protein, mediates PTEN-dependent apoptosis and cavitation. PTEN inactivation inhibits hypoxia-and reactive oxygen species-induced Bnip3 elevation. Overexpression of Bnip3 in PTEN-null EBs rescues apoptosis of the core cells. Mechanistically, suppression of Bnip3 following PTEN loss is likely due to reduction of hypoxia-inducible factor-2α (HIF-2α) because forced expression of an oxygen-stable HIF-2α mutant rescues Bnip3 expression and apoptosis. Lastly, we show that HIF-2α is upregulated by PTEN at both transcriptional and posttranscriptional levels. Ablation of prolyl hydroxylase domain-containing protein 2 (PHD2) in normal EBs or inhibition of PHD activities in PTEN-null EBs stabilizes HIF-2α and induces Bnip3 and caspase-3 activation. Altogether, these results suggest that PTEN is required for apoptosis-mediated cavitation during epithelial morphogenesis by regulating the expression of HIF-2α and Bnip3.

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“…• Experimental studies (Delcommenne & Streuli, 1995;Davis et al, 2001;Liu et al, 2011;Lobert et al, 2010) have shown that the half-lifes of the integrins range from 0.04 − 4 days. This corre- Table 2, of (a) Cancer cell density u 1 of the first ("normal") population; (b) Cancer cell density u 2 of the second ("mutant") population; (c) ECM density f ; (d) Integrin density c.…”

Section: Summary Of Model Variables and Parametersmentioning

confidence: 99%

Lyapunov–Schmidt and Centre Manifold Reduction Methods for Nonlocal PDEs Modelling Animal Aggregations

Buono

Eftimie

2016

Springer Proceedings in Mathematics &Amp; Statistics

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[Date] Cells adhere to each other and to the extracellular matrix (ECM) through protein molecules on the surface of the cells. The breaking and forming of adhesive bonds, a process critical in cancer invasion and metastasis, can be influenced by the mutation of cancer cells. In this paper, we develop a nonlocal mathematical model describing cancer cell invasion and movement as a result of integrin-controlled cell-cell adhesion and cell-matrix adhesion, for two cancer cell populations with different levels of mutation. The partial differential equations for cell dynamics are coupled with ordinary differential equations describing the extracellular matrix (ECM) degradation and the production and decay of integrins. We use this model to investigate the role of cancer mutation on the possibility of cancer clonal competition with alternating dominance, or even competitive exclusion (phenomena observed experimentally). We discuss different possible cell aggregation patterns, as well as travelling wave patterns. In regard to the travelling waves, we investigate the effect of cancer mutation rate on the speed of cancer invasion.

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Talin1 Regulates Integrin Turnover To Promote Embryonic Epithelial Morphogenesis

Cited by 37 publications

References 49 publications

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

PTEN induces apoptosis and cavitation via HIF-2-dependent Bnip3 upregulation during epithelial lumen formation

Lyapunov–Schmidt and Centre Manifold Reduction Methods for Nonlocal PDEs Modelling Animal Aggregations

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