Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair

Bock-Marquette, Ildiko; Saxena, Ankur; White, Michael; DiMaio, J. Michael; Srivastava, Deepak

doi:10.1038/nature03000

Cited by 624 publications

(690 citation statements)

References 37 publications

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“…Although in vivo approaches in murine models of myocardial infarction will have to be carried out to confirm whether AGHMT leads to significant improvements to the ischemic heart, the study by Zhou et al (9) opens important avenues to further elucidate the mechanisms and molecules involved in cardiomyocyte generation and maturation. The results presented are consistent with an earlier study that reported the beneficial effect of thymosin-β4, known to improve cardiac repair and activate AKT (12), in potentiating GMT-dependent cardiac reprogramming and improving heart function (13). The discovery that AKT signaling potentiates the cardiac reprogramming process is also consistent with the reported ability of AKT to promote the reprogramming of mouse primordial germ cells to an ESC-like state and, more recently, to generate induced pluripotent stem cells, at least in part, via the transcriptional activation of the pluripotent transcription factor Nanog (14,15).…”

Section: Akt Action In Cardiac Protection and Repairsupporting

confidence: 81%

Repairing hearts with AKT

Komati

Nemer

2015

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

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Section: Akt Action In Cardiac Protection and Repairsupporting

confidence: 81%

Repairing hearts with AKT

Komati

Nemer

2015

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

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“…iv) Furthermore, our results show several kinases related to the integrin signaling pathways were perturbed, including integrin-linked kinase (ILK), nuclear factor-κB (NF-κB), the epidermal growth factor receptor (EGFR), caveolin, etc. These proteins are closely associated with integrin regulation and cell migration (80). It has been reported that the overexpression of ILK could promote the migration and invasion of colorectal cancer cells via NF-κB signaling (81).…”

Section: Resultsmentioning

confidence: 99%

Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins

Ali

Tang

et al. 2017

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

164

113

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Metastasis is responsible for most cancer-related deaths, but the current clinical treatments are not effective. Recently, gold nanoparticles (AuNPs) were discovered to inhibit cancer cell migration and prevent metastasis. Rationally designed AuNPs could greatly benefit their antimigration property, but the molecular mechanisms need to be explored. Cytoskeletons are cell structural proteins that closely relate to migration, and surface receptor integrins play critical roles in controlling the organization of cytoskeletons. Herein, we developed a strategy to inhibit cancer cell migration by targeting integrins, using Arg-Gly-Asp (RGD) peptide-functionalized gold nanorods. To enhance the effect, AuNRs were further activated with 808-nm near-infrared (NIR) light to generate heat for photothermal therapy (PPTT), where the temperature was adjusted not to affect the cell viability/proliferation. Our results demonstrate changes in cell morphology, observed as cytoskeleton protrusions-i.e., lamellipodia and filopodia-were reduced after treatment. The Western blot analysis indicates the downstream effectors of integrin were attracted toward the antimigration direction. Proteomics results indicated broad perturbations in four signaling pathways, Rho GTPases, actin, microtubule, and kinases-related pathways, which are the downstream regulators of integrins. Due to the dominant role of integrins in controlling cytoskeleton, focal adhesion, actomyosin contraction, and actin and microtubule assembly have been disrupted by targeting integrins. PPTT further enhanced the remodeling of cytoskeletal proteins and decreased migration. In summary, the ability of targeting AuNRs to cancer cell integrins and the introduction of PPTT stimulated broad regulation on the cytoskeleton, which provides the evidence for a potential medical application for controlling cancer metastasis.gold nanorods | cytoskeleton | integrin | metastasis | plasmonic photothermal therapy

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“…Bock-Marquette et al (18) recently reported that PINCH-1 and ILK function as key regulators of cardiac cell migration, survival and repair. Furthermore, they have shown that PINCH-1, through its C-terminal region, interacts with thymosin ␤4 (18).…”

Section: Discussionmentioning

confidence: 99%

Molecular Dissection of PINCH-1 Reveals a Mechanism of Coupling and Uncoupling of Cell Shape Modulation and Survival

Fukuda

et al. 2005

Journal of Biological Chemistry

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How cells couple and uncouple regulation of cellular processes such as shape change and survival is an important question in molecular cell biology. PINCH-1, a widely expressed protein consisting of five LIM domains and a C-terminal tail, is an essential focal adhesion protein with multiple functions including regulation of the integrin-linked kinase (ILK) level, cell shape, and survival signaling. We show here that the LIM1-mediated interaction with ILK regulates all these three processes. By contrast, the LIM4-mediated interaction with Nck-2, which regulates cell morphology and migration, is not required for the control of the ILK level and survival. Remarkably, a short 15-residue tail C-terminal to LIM5 is required for both cell shape modulation and survival, albeit it is not required for the control of the ILK level. The C-terminal tail not only regulates PINCH-1 localization to focal adhesions but also functions after it localizes there. These findings suggest that PINCH-1 functions as a molecular platform for coupling and uncoupling diverse cellular processes via overlapping but yet distinct domain interactions. Cell-extracellular matrix (ECM)1 adhesion is a fundamental process that is critically involved in embryonic development and numerous physiological and pathological processes including injury repair, cancer, and organ (e.g. heart and renal) failure. Among key regulators of cell-ECM adhesion and signaling are proteins localized at the membrane-actin cytoskeleton junctions in cell-ECM contacts (e.g. focal adhesions). PINCH-1 is a widely expressed focal adhesion protein consisting of five LIM domains and a short residue C-terminal tail (for review, see Refs. 1-4). Recent biochemical, cell biological, and genetic studies have demonstrated that PINCH-1 is crucial for cell shape modulation and signal transduction (5-13). Furthermore, there is evidence suggesting that PINCH-1 could serve as a useful target for therapeutic intervention of human diseases such as cancer and organ (e.g. heart and renal) failure (2, 4, 14 -19). Elucidating the molecular mechanism whereby PINCH-1 functions, therefore, is important for understanding the general principle that governs the regulation of cell-ECM adhesion and signaling as well as for the development of new therapeutic approaches that control these processes.PINCH-1 interacts with ILK (5, 20, 21), an equally widely expressed focal adhesion component that is essential for integrin-mediated cell-ECM adhesion and signaling (for review, see Refs. 2-4, 22, and 23). The ILK-binding site has been mapped to the second zinc finger of the N-terminal-most LIM1 domain that contains 21,24). In addition, PINCH-1 interacts with Nck-2 (25, 26), an SH2/SH3-containing adaptor protein that is involved in both cell adhesion-and growth factormediated signaling and actin cytoskeleton remodeling (27-29). The Nck-2-binding site is located in the first zinc finger of the PINCH-1 C-terminal LIM4 domain (25,26). Recently, we have suppressed the expression of PINCH-1 and ILK, respectively, in ...

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Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair

Cited by 624 publications

References 37 publications

Repairing hearts with AKT

Repairing hearts with AKT

Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins

Molecular Dissection of PINCH-1 Reveals a Mechanism of Coupling and Uncoupling of Cell Shape Modulation and Survival

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