IPP Complex Reinforces Adhesion by Relaying Tension-Dependent Signals to Inhibit Integrin Turnover

Abstract

Cytoskeleton-mediated forces regulate the assembly and function of integrin adhesions; however, the underlying mechanisms remain unclear. The tripartite IPP complex, comprising ILK, Parvin, and PINCH, mediates the integrin-actin link at Drosophila embryo muscle attachment sites (MASs). Here, we demonstrate a developmentally earlier function for the IPP complex: to reinforce integrin-extracellular matrix (ECM) adhesion in response to tension. In IPP-complex mutants, the integrin-ECM linkage at MASs breaks in response to intense muscle contractility. Mechanistically, the IPP complex is required to relay force-elicited signals that decelerate integrin turnover at the plasma membrane so that the integrin immobile fraction is adequate to withstand tension. Epistasis analysis shows that alleviation of muscle contractility, downregulation of endocytosis, and enhanced integrin binding to the ECM are sufficient to restore integrin-ECM adhesion and maintain integrin-adhesome organization in IPP-complex mutants. Our findings reveal a role for the IPP complex as an essential mechanosensitive regulatory switch of integrin turnover in vivo.

Adipose tissue depot‐specific intracellular and extracellular cues contributing to insulin resistance in obese individuals

“…It is plausible that OM adipocytes in IR obese individuals are submitted to increased microenvironmental stiffness. This is supported by our observations showing higher β1‐integrin levels in IR obese OM fat, and our previous data 24 demonstrating an enrichment in IR obese OM adipocytes of the integrin adhesome component, integrin‐linked kinase, which couples intracellular mechanical forces with ECM stiffness 41 . Together, our findings suggest that integrin functions, that is, adipocyte anchoring to the ECM and ECM‐to‐cell mechanotransduction, are altered in IR obese OM fat, suggesting a role for disturbed ECM‐integrin interactions in obesity‐related metabolic complications.…”

“…This is supported by our observations showing higher β1-integrin levels in IR obese OM fat, and our previous data 24 demonstrating an enrichment in IR obese OM adipocytes of the integrin adhesome component, integrin-linked kinase, which couples intracellular mechanical forces with ECM stiffness. 41 Together, our findings suggest that integrin functions, that is, adipocyte anchoring to the ECM and ECMto-cell mechanotransduction, are altered in IR obese OM fat, suggesting a role for disturbed ECM-integrin interactions in F I G U R E 4 Three-Dimensional (3D) culture of 3T3-L1 adipocytes. Effects of lumican on COL-I fibrillogenesis and mechanical properties of COL-I matrices.…”

Optineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division

“…Beta1 integrin studies show higher endocytosis on soft ECM, as exemplified by experiments conducted on mesenchymal stem cells cultured on collagen, showing enhanced caveolae and Raft-dependent endocytosis on soft ECM 83 . Similarly, the ILK-Pinch-Parvin complex (IPP) reinforces integrin-ECM adhesion in Drosophila embryos in response to tension and decelerates integrin turnover at the plasma membrane 84 . Bacterial invasion being higher on high stiffness ECM, a direct parallel with a diversion of integrin endocytosis by bacteria for their uptake seems paradoxical in the actual state of knowledge.…”

PINCH1 Promotes Fibroblast Migration in Extracellular Matrices and Influences Their Mechanophenotype

“…Subsequently through this actin-myosin filament interplay cellular mechanical characteristics, such as cell stiffness and viscoelasticity, may be impacted. In reaction to tension, the IPP complex has been considered to exert a developmentally antecedent role or function: It strengthens the attachment between integrins and extracellular matrix ( Vakaloglou et al, 2016 ). However, in IPP complex mutants, the connection between integrin and extracellular matrix ruptures due to elevated muscle contraction in muscle attachment sites ( Vakaloglou et al, 2016 ).…”

“…In reaction to tension, the IPP complex has been considered to exert a developmentally antecedent role or function: It strengthens the attachment between integrins and extracellular matrix ( Vakaloglou et al, 2016 ). However, in IPP complex mutants, the connection between integrin and extracellular matrix ruptures due to elevated muscle contraction in muscle attachment sites ( Vakaloglou et al, 2016 ). From a mechanistic point of view, the IPP complex is necessary to transduce force-evoked cues that slow down the integrin turnover across the plasma membrane, so that the immobile integrin moiety is sufficient to sustain stresses.…”