ICAP-1 monoubiquitination coordinates matrix density and rigidity sensing for cell migration through ROCK2- MRCKα balance

Cell migration is a complex process requiring density and rigidity sensing of the microenvironment to adapt cell migratory speed through focal adhesion and actin cytoskeleton regulation. ICAP-1, a β1 integrin partner, is essential for ensuring integrin activation cycle and focal adhesion formation. We show that ICAP-1 is monoubiquitinated by Smurf1, preventing ICAP-1 binding to β1 integrin. The non-ubiquitinable form of ICAP-1 modifies β1 integrin focal adhesion organization and interferes with fibronectin density sensing. ICAP-1 is also required for adapting cell migration in response to substrate stiffness in a β1 integrin-independent manner. ICAP-1 monoubiquitination regulates rigidity sensing by increasing MRCKα-dependent cell contractility through myosin phosphorylation independently of substrate rigidity. We provide evidence that ICAP-1 monoubiquitination helps in switching from ROCK2-mediated to MRCKα-mediated cell contractility. ICAP-1 monoubiquitination serves as a molecular switch to coordinate extracellular matrix density and rigidity sensing thus acting as a critical modulator of cell migration and mechanosensing.