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

J Cell Sci. 2017 Feb 1;130(3):626-636. doi: 10.1242/jcs.200139. Epub 2017 Jan 3.

Abstract

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 (also known as ITGB1BP1), a β1 integrin partner, is essential for ensuring integrin activation cycle and focal adhesion formation. We show that ICAP-1 is monoubiquitylated by Smurf1, preventing ICAP-1 binding to β1 integrin. The non-ubiquitylatable 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 monoubiquitylation regulates rigidity sensing by increasing MRCKα (also known as CDC42BPA)-dependent cell contractility through myosin phosphorylation independently of substrate rigidity. We provide evidence that ICAP-1 monoubiquitylation helps in switching from ROCK2-mediated to MRCKα-mediated cell contractility. ICAP-1 monoubiquitylation serves as a molecular switch to coordinate extracellular matrix density and rigidity sensing thus acting as a crucial modulator of cell migration and mechanosensing.

Keywords: Cell contractility; Cell migration; ICAP-1; Integrin; Monoubiquitylation; Rigidity sensing.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Binding Sites
  • Biomechanical Phenomena
  • Cell Adhesion
  • Cell Line
  • Cell Movement*
  • Extracellular Matrix / metabolism*
  • Fibronectins / metabolism
  • Focal Adhesions / metabolism
  • Humans
  • Integrin beta1 / chemistry
  • Integrin beta1 / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • Models, Biological
  • Myotonin-Protein Kinase / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination*
  • rho-Associated Kinases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Fibronectins
  • ICAP-1 protein, mouse
  • ITGB1BP1 protein, human
  • Integrin beta1
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SMURF1 protein, human
  • Ubiquitin-Protein Ligases
  • CDC42BPA protein, human
  • Myotonin-Protein Kinase
  • ROCK2 protein, human
  • rho-Associated Kinases