Flightless anchors IQGAP1 and R-ras to mediate cell extension formation and matrix remodeling

Arora, Pamma D.; Nakajima, Kei; Nanda, Arvind; Plaha, A; Wilde, Andrew; Sacks, David B.; McCulloch, Christopher A.

doi:10.1091/mbc.e19-10-0554

Cited by 15 publications

(22 citation statements)

References 56 publications

(69 reference statements)

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“…FliI expression affects remodeling of collagen because of the central role of FliI in regulating the formation of cell extensions that extend into the extracellular collagen matrix (Arora et al, 2020). These cell extensions are essential for the degradation of collagen fibers by phagocytosis (Melcher & Chan, 1981).…”

Section: Resultsmentioning

confidence: 99%

“…FliI (Arora et al, 2020). Here we examined the role of IQGAP1 in collagen remodeling through its impact on collagen phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

“…The degradation of collagen fibers requires extracellular matrix metalloproteinases or the cathepsin‐dependent phagocytic pathway (Melcher & Chan, 1981). A multidomain, small GTPase activating protein, IQGAP1, is thought to be involved in the generation of cell extensions required for collagen phagocytosis, which involves the stabilization and localization of cdc42 and its interaction with the actin capping and severing protein FliI (Arora et al, 2020). Here we examined the role of IQGAP1 in collagen remodeling through its impact on collagen phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

“…The generation of cell extensions and the degradation of collagen by fibroblasts critically involves assembly and reorganization of actin filaments by proteins that sever and cap growing filaments. One member of the gelsolin family of actin severing and capping proteins is Flightless I (FliI; Arora, Wang, Bresnick, Janmey, & McCulloch, 2015), which plays a critical role in collagen degradation by phagocytosis (Arora, Di Gregorio, He, & McCulloch, 2017) and also acts as an adapter protein that binds and coordinates with IQGAP1 and cdc42 to control the formation of cell extensions (Arora et al, 2020). Here, we examined the role of IQGAP1 and its coordination with FliI to regulate collagen degradation by phagocytosis.…”

Section: Introductionmentioning

confidence: 99%

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Role of the small GTPase activating protein IQGAP1 in collagen phagocytosis

Nakajima

Arora

Plaha

et al. 2020

Journal Cellular Physiology

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Many adult connective tissues undergo continuous remodeling to maintain matrix homeostasis. Physiological remodeling involves the degradation of collagen fibers by the intracellular cathepsin-dependent phagocytic pathway. We considered that a multidomain, small GTPase activating protein, IQGAP1, which is involved in the generation of cell extensions, is required for collagen phagocytosis, possibly arising from its interactions with cdc42 and the actin-binding protein Flightless I (FliI). We examined the role of IQGAP1 in collagen phagocytosis by human gingival fibroblasts (HGFs) and by IQGAP1+/+ and IQGAP1−/− mouse embryonic fibroblasts. IQGAP1 was strongly expressed by HGFs, localized to vinculin-stained cell adhesions and sites where cell extensions are initiated, and colocalized with FliI. Immunoprecipitation showed that IQGAP1 associated with FliI. HGFs showed 10-fold increases of collagen binding, 6-fold higher internalization, and 3-fold higher β1 integrin activation between 30 and 180 min after incubation with collagen. Compared with IQGAP1+/+ fibroblasts, deletion of IQGAP1 reduced collagen binding (1.4-fold), collagen internalization (3-fold), β1 integrin activation (2-fold), and collagen degradation (1.8-fold). We conclude that IQGAP1 affects collagen remodeling through its regulation of phagocytic degradation pathways, which may involve the interaction of IQGAP1 with FliI.

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Section: Resultsmentioning

confidence: 99%

“…FliI (Arora et al, 2020). Here we examined the role of IQGAP1 in collagen remodeling through its impact on collagen phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of the small GTPase activating protein IQGAP1 in collagen phagocytosis

Nakajima

Arora

Plaha

et al. 2020

Journal Cellular Physiology

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“…Recent studies have further shown that explanted tendons from Flii overexpressing mice have significantly elevated tenocyte outgrowth compared to Flii +/− mice [20]. In addition, there is a large body of evidence showing the importance of Flii in cellular adhesion and matrix remodelling [21][22][23] as well as tissue inflammation during wound healing and in inflammatory skin conditions [24][25][26][27][28], consequently, here, we investigated the effect of altering Flii expression in vivo on tendon adhesion formation. A murine model of tendon adhesion was used in these studies and conducted using a partial laceration of the digital flexor tendon in the third and fourth digit of both hind-paws, in conjunction with a full tenotomy to immobilise the digits of the paw [29].…”

Section: Introductionmentioning

confidence: 98%

Increasing the level of cytoskeletal protein Flightless I reduces adhesion formation in a murine digital flexor tendon model

et al. 2020

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Background: Surgical repair of tendons is common, but function is often limited due to the formation of flexor tendon adhesions which reduce the mobility and use of the affected digit and hand. The severity of adhesion formation is dependent on numerous cellular processes many of which involve the actin cytoskeleton. Flightless I (Flii) is a highly conserved cytoskeletal protein, which has previously been identified as a potential target for improved healing of tendon injuries. Using human in vitro cell studies in conjunction with a murine model of partial laceration of the digital flexor tendon, we investigated the effect of modulating Flii levels on tenocyte function and formation of adhesions. Methods: Human tenocyte proliferation and migration was determined using WST-1 and scratch wound assays following Flii knockdown by siRNA in vitro. Additionally, mice with normal and increased levels of Flii were subjected to a partial laceration of the digital flexor tendon in conjunction with a full tenotomy to immobilise the paw. Resulting adhesions were assessed using histology and immunohistochemistry for collagen I, III, TGF-β1and-β3 Results: Flii knockdown significantly reduced human tenocyte proliferation and migration in vitro. Increasing the expression of Flii significantly reduced digital tendon adhesion formation in vivo which was confirmed through significantly smaller adhesion scores based on collagen fibre orientation, thickness, proximity to other fibres and crimping. Reduced adhesion formation was accompanied with significantly decreased deposition of type I collagen and increased expression of TGF-β1 in vivo. Conclusions: These findings suggest that increasing the level of Flii in an injured tendon may be beneficial for decreasing tendon adhesion formation.

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High Endothelial Venules Accelerate Naive T Cell Recruitment by Tumor Necrosis Factor-Mediated R-Ras Upregulation

Sawada

Perrot

Chen

et al. 2021

The American Journal of Pathology

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Flightless anchors IQGAP1 and R-ras to mediate cell extension formation and matrix remodeling

Abstract: The actin-binding protein Flightless I interacts with IQGAP1 to coordinate the formation of collagen-remodeling cell extensions, a process which is mediated by the activities of cdc42 and R-ras.

Cited by 15 publications

References 56 publications

Role of the small GTPase activating protein IQGAP1 in collagen phagocytosis

Role of the small GTPase activating protein IQGAP1 in collagen phagocytosis

Increasing the level of cytoskeletal protein Flightless I reduces adhesion formation in a murine digital flexor tendon model

High Endothelial Venules Accelerate Naive T Cell Recruitment by Tumor Necrosis Factor-Mediated R-Ras Upregulation

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