Integrin-linked kinase (ILK) is required for polarizing the epiblast, cell adhesion, and controlling actin accumulation

Sakai, Takao; Li, Shaohua; Docheva, Denitsa; Grashoff, Carsten; Sakai, Keiko; Kostka, Günter; Braun, Attila; Pfeifer, Alexander; Yurchenco, Peter D.; Fässler, Reinhard

doi:10.1101/gad.255603

Cited by 357 publications

(364 citation statements)

References 45 publications

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“…The Pinch null mouse survives slightly longer (E6.5-E7.5) than the Ilk null mouse (E5.5-E6.5). Furthermore, Pinch null embryoid bodies display additional defects in cell-cell adhesion of the endoderm and the epiblast and contain apoptotic cells within the endodermal layer that are not seen in embryoid bodies derived from Ilk null embryos (Sakai et al, 2003;Li et al, 2005). Genetic studies in Drosophila also support the view that ILK and PINCH, though performing many common functions, have some unique and independent roles.…”

Section: Introductionmentioning

confidence: 80%

“…In the mouse, targeted gene disruption of either Pinch or Ilk results in embryonic lethality at the peri-implantation stage. Embryoid bodies derived from Pinch and Ilk null embryos display abnormal epiblast polarity, impaired cavitation, and detachment of the endoderm and epiblast from the basement membrane (Sakai et al, 2003;Li et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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A critical role for Ras Suppressor-1 (RSU-1) revealed when PINCH-Integrin-linked Kinase (ILK) binding is disrupted

Elias

Pronovost

Cahill

et al. 2012

Journal of Cell Science

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Summary PINCH, integrin-linked kinase (ILK) and Ras suppressor-1 (RSU-1) are molecular scaffolding proteins that form a physical complex downstream of integrins, and have overlapping roles in cellular adhesion. In Drosophila, PINCH and ILK colocalize in cells and have indistinguishable functions in maintaining wing adhesion and integrin to actin linkage in the muscle. We sought to determine whether the direct physical interaction between PINCH and ILK was essential for their functions using transgenic flies expressing a version of PINCH with a point mutation that disrupts ILK binding (PINCH Q38A ). We demonstrate that the PINCH-ILK interaction is not required for viability, for integrin-mediated adhesion of the wing or muscle, or for maintaining appropriate localization or levels of either PINCH or ILK. These results suggest alternative modes for PINCH localization, stabilization and linkage to the actin cytoskeleton that are independent of a direct interaction with ILK. Furthermore, we identified a synthetic lethality in flies carrying both the PINCH Q38A mutation and a null mutation in the gene encoding RSU-1. This lethality does not result from PINCH mislocalization or destabilization, and illustrates a novel compensatory role for RSU-1 in maintaining viability in flies with compromised PINCH-ILK binding. Taken together, this work highlights the existence of redundant mechanisms in adhesion complex assembly that support integrin function in vivo.

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Section: Introductionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

A critical role for Ras Suppressor-1 (RSU-1) revealed when PINCH-Integrin-linked Kinase (ILK) binding is disrupted

Elias

Pronovost

Cahill

et al. 2012

Journal of Cell Science

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“…Western-blot analyses were performed as described. 20 In some immunoblotting analyses, samples were transferred onto Immobilon-FL PDVF membrane (Millipore Corp., Temecula, CA) and probed with primary and IRDye 800CW-or IRDye 680-conjugated secondary antibodies (LI-COR Bioscience, Lincoln, NE). Immunoreactive bands were detected using the Odyssey Infrared Imaging System (LI-COR Bioscience) as described previously.…”

Section: One-and Two-dimensional Sds-page and Western Blot Analysismentioning

confidence: 99%

Critical Role of Factor XIII in the Initial Stages of Carbon Tetrachloride–Induced Adult Liver Remodeling

Tsujimoto

Moriya

Sakai

et al. 2011

The American Journal of Pathology

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The transglutaminase-mediated, covalent cross-linking of proteins is an essential step in tissue remodeling after injury. This process provides tissues with extra rigidity and resistance against proteolytic degradation. Plasma coagulation factor XIII (FXIII) is a transglutaminase that promotes cross-linking of the extracellular matrix (ECM) components fibrin and fibronectin to form a provisional matrix in response to tissue damage. However, the functional requirement for this FXIII-mediated cross-linked provisional matrix in adult tissue remodeling remains to be defined. Although it has been proposed that the formation FXIII-mediated fibrin-fibronectin provisional matrix is a critical step for ECM remodeling, we show in an FXIII subunit A-deficient murine model of acute liver injury that the lack of FXIII subunit A did not interfere with collagen reconstruction and resolution after liver injury. Furthermore, FXIIIA deficiency caused significantly increased hepatocyte apoptosis and a delay in hepatocyte regeneration after injury, which were accompanied by a significantly high induction of p53 expression. These findings suggest novel functions of FXIII that the FXIII-mediated covalently crosslinked matrix could promote survival signals for hepatocytes in adult tissue remodeling. Covalent cross-linking between proteins, including in the provisional matrix, is catalyzed by transglutaminases (TGs). This is an important process for tissue remodeling as it generates extra rigidity and a resistance against proteolytic degradation. 1 Plasma coagulation factor Xlll (FXlll), one of the TG family members, circulates as a heterotetramer composed of two catalytic A subunits (FXIII A) and two noncatalytic B subunits (FXIII B) (A 2 B 2 ), which are activated by thrombinmediated cleavage. FXlll is a Ca 2ϩ -dependent TG and catalyzes the formation of -(␥-glutamyl) lysyl crosslinks between specific protein pairs. The cross-linking of fibrin molecules by FXIII to form ␥-chain dimerization is the final step of blood coagulation. 2-4 FXIII also acts on fibronectin-fibronectin and fibrin-fibronectin cross-linking. 5,6 Thus, the action of FXIII in forming covalent crosslinkages clearly plays a vital role in establishing the mechanical stability of the clot, which is critical for homeostatic functions. 2,4 Growing evidence demonstrates that the source of FXIII is not only from plasma: Megakaryocytes/ platelets and monocytes/macrophages also contain cellular FXIII subunit A in their cytoplasm. 7,8 Acute liver injury mediated by the hepatitis virus or hepatotoxins causes massive hepatocyte apoptosis and/or fatal liver damage, and eventually liver transplantation is required. 9,10 Identification of hepatic survival factors is critical for successful therapeutic intervention in liver failure. After acute injury, the liver undergoes a wound-healing response to restore tissue architecture and maintain homeostasis. 11 It requires both a well-orchestrated proliferation of cells and the reconstruction of the extracellular matrix (ECM). A central...

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“…These findings suggested the existence of compensatory integrin/dystroglycan/ECM mechanisms for epiblast development . Mediators of polarization downstream of the basement membrane were found to include integrin-linked kinase, PINCH-1, Rac1 and Cdc42 and kindlin-2 (Sakai et al 2003;Li et al 2005a;Wu et al 2007;Montanez et al 2008;He et al 2010). …”

Section: Early Morphogenesismentioning

confidence: 99%

Basement Membranes: Cell Scaffoldings and Signaling Platforms

Yurchenco

2010

Cold Spring Harbor Perspectives in Biology

780

775

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Integrin-linked kinase (ILK) is required for polarizing the epiblast, cell adhesion, and controlling actin accumulation

Cited by 357 publications

References 45 publications

A critical role for Ras Suppressor-1 (RSU-1) revealed when PINCH-Integrin-linked Kinase (ILK) binding is disrupted

A critical role for Ras Suppressor-1 (RSU-1) revealed when PINCH-Integrin-linked Kinase (ILK) binding is disrupted

Critical Role of Factor XIII in the Initial Stages of Carbon Tetrachloride–Induced Adult Liver Remodeling

Basement Membranes: Cell Scaffoldings and Signaling Platforms

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