Flightless I interacts with NMMIIA to promote cell extension formation, which enables collagen remodeling

Arora, Pamma D.; Wang, Yongqiang; Bresnick, Anne R.; Janmey, Paul A.; McCulloch, Christopher A.

doi:10.1091/mbc.e14-11-1536

Cited by 22 publications

(27 citation statements)

References 90 publications

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“…Our data also indicates that P-Rex1-mediated cell contraction is important for collagen crosslinking and remodelling. We propose that P-Rex1-induced collagen remodelling is also dependent on FLII since FLII has recently been shown to interact with nonmuscle myosin IIA (NMMIIA) at cell protrusions, which is important for cell extension formation that enables FLII-dependent collagen remodelling by fibroblasts 67 . Given the link between ECM remodelling and cancer metastasis (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration

Marei¹,

Carpy²,

Woroniuk³

et al. 2016

Nat Commun

108

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The small GTPase Rac1 has been implicated in the formation and dissemination of tumours. Upon activation by guanine nucleotide exchange factors (GEFs), Rac1 associates with a variety of proteins in the cell thereby regulating various functions, including cell migration. However, activation of Rac1 can lead to opposing migratory phenotypes raising the possibility of exacerbating tumour progression when targeting Rac1 in a clinical setting. This calls for the identification of factors that influence Rac1-driven cell motility. Here we show that Tiam1 and P-Rex1, two Rac GEFs, promote Rac1 anti- and pro-migratory signalling cascades, respectively, through regulating the Rac1 interactome. In particular, we demonstrate that P-Rex1 stimulates migration through enhancing the interaction between Rac1 and the actin-remodelling protein flightless-1 homologue, to modulate cell contraction in a RhoA-ROCK-independent manner.

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Section: Discussionmentioning

confidence: 99%

Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration

Marei¹,

Carpy²,

Woroniuk³

et al. 2016

Nat Commun

108

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“…, 2012 ) and regulates the growth of extensions in cells plated on collagen. The GLDs in the C-terminal of FliI interact with nonmuscle myosin IIA to regulate collagen remodeling ( Arora et al. , 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…, 1996 ). To enable phagocytosis of collagen, which is the main structural protein of the ECM ( Perez-Tamayo, 1978 ), fibroblasts reorganize subcortical actin filaments to generate plasma membrane extensions that engulf collagen fibrils ( Arora et al. , 2015 ).…”

Section: Introductionmentioning

confidence: 99%

The leucine-rich region of Flightless I interacts with R-ras to regulate cell extension formation

Arora

Torebjörk

et al. 2018

MBoC

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Flightless I (FliI) is a calcium-dependent, actin severing and capping protein that localizes to cell matrix adhesions, contributes to the generation of cell extensions, and colocalizes with Ras. Currently, the mechanism by which FliI interacts with Ras to enable assembly of actin-based cell protrusions is not defined. R-Ras, but not K-ras, H-ras, or N-ras, associated with the leucine-rich region (LRR) of FliI. Mutations of the proline-rich region of R-ras (P202A, P203A) prevented this association. Knockdown of Ras GTPase-activating SH3 domain-binding protein (G3BP1) or Rasgap120 by small interfering RNA inhibited the formation of cell extensions and prevented interaction of R-ras and G3BP1 in FliI wild-type (WT) cells. Pull-down assays using G3BP1 fusion proteins showed a strong association of R-ras with the C-terminus of G3BP1 (amino acids 236–466), which also required the LRR of FliI. In cells that expressed the truncated N-terminus or C-terminus of G3BP1, the formation of cell extensions was blocked. Endogenous Rasgap120 interacted with the N-terminus of G3BP1 (amino acids 1–230). We conclude that in cells plated on collagen FliI-LRR interacts with R-ras to promote cell extension formation and that FliI is required for the interaction of Rasgap120 with G3BP1 to regulate R-ras activity and growth of cell extensions.

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“…Additionally, a separate pool of phosphorylated MLC has also been described at the leading edge of motile cells 21,44 . Interestingly, FLII was shown to regulate the activation of nonmuscle myosin IIA (NMMIIA) at cell protrusions to promote the formation of cell extensions that mediate collagen remodeling 45 . This suggests that FLII might regulate cell contraction at the leading edge in a RhoA-ROCK-independent manner.…”

Section: Gefs As Master Regulators Of Rac1 Signalingmentioning

confidence: 99%

GEFs: Dual regulation of Rac1 signaling

Marei

Malliri

2016

Small GTPases

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GEFs play a critical role in regulating Rac1 signaling. They serve as signaling nodes converting upstream signals into downstream Rac1-driven cellular responses. Through associating with membrane-bound Rac1, GEFs facilitate the exchange of GDP for GTP, thereby activating Rac1. As a result, Rac1 undergoes conformational changes that mediate its interaction with downstream effectors, linking Rac1 to a multitude of physiological and pathological processes. Interestingly, there are at least 20 GEFs involved in Rac1 activation, suggesting a more complex role of GEFs in regulating Rac1 signaling apart from promoting the exchange of GDP for GTP. Indeed, accumulating evidence implicates GEFs in directing the specificity of Rac1-driven signaling cascades, although the underlying mechanisms were poorly defined. Recently, through conducting a comparative study, we highlighted the role of 2 Rac-specific GEFs, Tiam1 and P-Rex1, in dictating the biological outcome downstream of Rac1. Importantly, further proteomic analysis uncovered a GEF activity-independent function for both GEFs in modulating the Rac1 interactome, which results in the stimulation of GEF-specific signaling cascades. Here, we provide an overview of our recent findings and discuss the role of GEFs as master regulators of Rac1 signaling with a particular focus on GEF-mediated modulation of cell migration following Rac1 activation.

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Flightless I interacts with NMMIIA to promote cell extension formation, which enables collagen remodeling

Abstract: The role of the actin-capping protein flightless I in collagen remodeling by mouse fibroblasts is examined. Flightless and nonmuscle myosin IIA cooperate to enable collagen phagocytosis.

Cited by 22 publications

References 90 publications

Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration

Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration

The leucine-rich region of Flightless I interacts with R-ras to regulate cell extension formation

GEFs: Dual regulation of Rac1 signaling

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