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A proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting.

ABSTRACT: Integrin activation, which is regulated by allosteric changes in receptor conformation, enables cellular responses to the chemical, mechanical and topological features of the extracellular microenvironment. A global view of how activation state converts the molecular composition of the region proximal to integrins into functional readouts is, however, lacking. Here, using conformation-specific monoclonal antibodies, we report the isolation of integrin activation state-dependent complexes and their characterization by mass spectrometry. Quantitative comparisons, integrating network, clustering, pathway and image analyses, define multiple functional protein modules enriched in a conformation-specific manner. Notably, active integrin complexes are specifically enriched for proteins associated with microtubule-based functions. Visualization of microtubules on micropatterned surfaces and live cell imaging demonstrate that active integrins establish an environment that stabilizes microtubules at the cell periphery. These data provide a resource for the interrogation of the global molecular connections that link integrin activation to adhesion signalling.

SUBMITTER: Byron A

PROVIDER: S-EPMC4317495 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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A proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting.

Byron Adam A Askari Janet A JA Humphries Jonathan D JD Jacquemet Guillaume G Koper Ewa J EJ Warwood Stacey S Choi Colin K CK Stroud Matthew J MJ Chen Christopher S CS Knight David D Humphries Martin J MJ

Nature communications 20150122

Integrin activation, which is regulated by allosteric changes in receptor conformation, enables cellular responses to the chemical, mechanical and topological features of the extracellular microenvironment. A global view of how activation state converts the molecular composition of the region proximal to integrins into functional readouts is, however, lacking. Here, using conformation-specific monoclonal antibodies, we report the isolation of integrin activation state-dependent complexes and the ...[more]

PMID: 25609142

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Project description:The â??small perturbationâ?? approach is critical in studying the â??steady stateâ?? of a biological system. In our experiments, small perturbations were generated by applying a series of repeating intermittent small doses of ultraviolet radiation to a human keratinocyte cell line, HaCaT. The biological response was assessed by monitoring the gene expression profiles using a high reliability and high resolution cDNA microarray system. Following intermittent 10 J/m2 UVB small perturbations, two opposite classes of genes, down-regulated and up-regulated, exhibited an immediate response followed by relaxation between each small perturbation, but were prolonged down- or up-regulated without relaxation while larger doses (233 or 582.5 J/m2) of UVB were applied. A repeated cycle pattern of gene expression following small perturbations is an indication of the existence of steady states. This cycle pattern is suppressed when large perturbations are applied. We believe that this is a universal phenomenon. In our experiments, the functions of up-regulated genes were mainly associated with anti-proliferation, anti-mitogenesis, and apoptosis. On the other hand, down-regulated genes were mainly related to proliferation, mitogenesis, and anti-apoptosis. In conclusion, this study experimentally proves the concept of steady state at the transcription level and demonstrates the feasibility of using small perturbation approaches for investigating steady states. This study could also set a foundation of computational systems biology, which has implicitly used the concept of steady state. Keywords: time course Three UVB exposures are indicated by UV at time points of 0, 8 and 16 hours. T1, T2, T3, T4, T5, and T6 denote the sampling time points. T1, T3 and T5 are allocated 30 minutes after the corresponding UVB irradiation. T2, T4 and T6 are allocated 8 hours after each UVB irradiation. At each sampling time point, two samples (control and UV-irradiated) are collected. See supplementary file Loop_design.pdf for further explanation.

Dataset Information

A proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting.

Publications

A proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting.

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