A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions.

Nisha Bte Mohd Rafiq; Yukako Nishimura; Sergey V. Plotnikov; Visalatchi Thiagarajan; Zhen Zhang; Shidong Shi; Meenubharathi Natarajan; Virgile Viasnoff; Pakorn Kanchanawong; Gareth E Jones; Alexander D. Bershadsky

doi:10.1038/s41563-019-0371-y

A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions.

Nisha Bte Mohd Rafiq, Yukako Nishimura, Sergey V. Plotnikov, Visalatchi Thiagarajan, Zhen Zhang, Shidong Shi, Meenubharathi Natarajan, Virgile Viasnoff, Pakorn Kanchanawong, Gareth E Jones, Alexander D. Bershadsky

Randall Centre of Cell & Molecular Biophysics

Mechanobiology Institute National University of Singapore

Research output: Contribution to journal › Article › peer-review

116 Citations (Scopus)

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Abstract

The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.

Original language	English
Pages (from-to)	638-649
Number of pages	12
Journal	NATURE MATERIALS
Volume	18
Issue number	6
Early online date	21 May 2019
DOIs	https://doi.org/10.1038/s41563-019-0371-y
Publication status	Published - 1 Jun 2019

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A mechano-signalling network_RAFIQ_Accepted10April2019_pub21May2019_GREEN AAMAccepted author manuscript, 46.4 MB

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title = "A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions.",

abstract = "The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.",

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AU - Thiagarajan, Visalatchi

AU - Zhang, Zhen

AU - Shi, Shidong

AU - Natarajan, Meenubharathi

AU - Viasnoff, Virgile

AU - Kanchanawong, Pakorn

AU - Jones, Gareth E

AU - Bershadsky, Alexander D.

PY - 2019/6/1

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N2 - The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.

AB - The interrelationship between microtubules and the actin cytoskeleton in mechanoregulation of integrin-mediated adhesions is poorly understood. Here, we show that the effects of microtubules on two major types of cell-matrix adhesion, focal adhesions and podosomes, are mediated by KANK family proteins connecting the adhesion protein talin with microtubule tips. Both total microtubule disruption and microtubule uncoupling from adhesions by manipulations with KANKs trigger a massive assembly of myosin IIA filaments, augmenting focal adhesions and disrupting podosomes. Myosin IIA filaments are indispensable effectors in the microtubule-driven regulation of integrin-mediated adhesions. Myosin IIA filament assembly depends on Rho activation by the RhoGEF GEF-H1, which is trapped by microtubules when they are connected with integrin-mediated adhesions via KANK proteins but released after their disconnection. Thus, microtubule capture by integrin-mediated adhesions modulates the GEF-H1-dependent effect of microtubules on the assembly of myosin IIA filaments. Subsequent actomyosin reorganization then remodels the focal adhesions and podosomes, closing the regulatory loop.

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A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions.

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Publisher Correction: A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions (Nature Materials, (2019), 18, 6, (638-649), 10.1038/s41563-019-0371-y)

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