Mechanism of IRSp53 inhibition and combinatorial activation by Cdc42 and downstream effectors

@article{Kast2014MechanismOI,
  title={Mechanism of IRSp53 inhibition and combinatorial activation by Cdc42 and downstream effectors},
  author={David J. Kast and Changsong Yang and Andrea Disanza and Malgorzata Boczkowska and Yadaiah Madasu and Giorgio Scita and Tatyana M. Svitkina and Roberto Dominguez},
  journal={Nature Structural \&Molecular Biology},
  year={2014},
  volume={21},
  pages={413-422}
}
The Rho family GTPase effector IRSp53 has essential roles in filopodia formation and neuronal development, but its regulatory mechanism is poorly understood. [] Key Result Using a fluorescence reporter assay, we show that human IRSp53 adopts a closed inactive conformation that opens synergistically with the binding of human Cdc42 to the CRIB–PR and effector proteins, such as the tumor-promoting factor Eps8, to the SH3 domain.
Mechanism of IRSp53 inhibition by 14-3-3
TLDR
A mechanism of phosphorylation-dependent inhibition of IR Sp53 by 14-3-3 is elucidated, which impedes the interactions of IRSp53 with membranes and downstream cytoskeletal effectors.
IRSp53 coordinates AMPK and 14-3-3 signaling to regulate filopodia dynamics and directed cell migration
TLDR
It is shown that phosphorylation-dependent inhibition of IRSp53 by 14-3-3 counters activation by Cdc42 and cytoskeletal effectors, resulting in down-regulation of filopodia dynamics and cancer cell migration.
Missing-in-metastasis protein downregulates CXCR4 by promoting ubiquitylation and interaction with small Rab GTPases
TLDR
It is shown that MIM forms a complex with CXCR4 by binding to E3 ubiquitin ligase AIP4 (also known as ITCH) in response to stromal cell-derived factor 1 (SDF-1; also known as CXCL12).
Coordinated autoinhibition of F-BAR domain membrane binding and WASp activation by Nervous Wreck
TLDR
Structural rearrangements in Nwk are defined that control F-BAR–membrane interactions as well as SH3 domain activities, and suggest that these two functions are tightly coordinated in vitro and in vivo.
Redundant functions of I-BAR family members, IRSp53 and IRTKS, are essential for embryonic development
TLDR
A hitherto under-appreciated IRSp53 function in embryonic development is demonstrated, and an essential genetic interaction between IR Sp53 and its closest family member, IRTKS, in placental formation is established.
Activated I-BAR IRSp53 clustering controls the formation of VASP-actin-based membrane protrusions
TLDR
A regulation mechanism of IRSp53 in its attributes of curvature sensation and partner recruitment is supported to ensure a precise spatial-temporal control of filopodia initiation.
The structure of FMNL2–Cdc42 yields insights into the mechanism of lamellipodia and filopodia formation
TLDR
The crystal structures of the N-terminal domains of human FMNL1 and FMNL2 in complex with active CDC42 show that Cdc42 mediates contacts with all five armadillo repeats of the formin with specific interactions formed by the Rho-GTPase insert helix.
SH2B1 increases the numbers of IRSp53-induced filopodia.
Small GTPases and BAR domain proteins regulate branched actin polymerisation for clathrin and dynamin-independent endocytosis
TLDR
It is shown that small GTPases and BAR domain proteins regulate branched actin to make clathrin and dynamin-independent endocytic vesicles.
BIN1 Membrane Curvature Sensing and Generation Show Autoinhibition Regulated by Downstream Ligands and PI(4,5)P2
TLDR
The results suggest an autoinhibition model for BIN1 that involves a synergistic regulation by membrane composition and protein–protein interactions.
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TLDR
It is demonstrated that IRSp53, a substrate for insulin receptor with unknown function, is the ‘missing link’ between Rac and WAVE, and is essential for Rac to induce membrane ruffling, which stimulates actin polymerization mediated by the Arp2/3 complex.
Tiam1-IRSp53 Complex Formation Directs Specificity of Rac-Mediated Actin Cytoskeleton Regulation
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Tiam1 not only activates Rac but also contributes to Rac signaling specificity through binding to IRSp53, an adaptor protein that is an effector for both Rac and Cdc42.
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It is proposed that IRSp53 generates filopodia by coupling membrane protrusion through its I-BAR domain with actin dynamics through SH3 domain binding partners, including N-WASP and Mena.
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TLDR
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TLDR
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TLDR
The findings implicate the importance of the IRSp53/Eps8 complex in Rac activation and metastatic behavior of the malignant tumor cells.
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TLDR
It is shown for the first time that IRSp53, through its interaction with Eps8, not only affects cell migration but also dictates cellular growth in cancer cells.
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TLDR
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Structure of Cdc42 in complex with the GTPase-binding domain of the ‘Wiskott–Aldrich syndrome’ protein
TLDR
Structural and biochemical data suggest that GBD-sequence divergence outside the CRIB motif may reflect additional regulatory interactions with functional domains that are specific to individual effectors.
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