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The α1 integrin cytoplasmic tail interacts with phosphoinositides and interferes with Akt activation

Josephine Labus1, Kerstin Tang2, Petra Henklein3

  • 1Institute for Biochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; Hannover Medical School, Department of Cellular Neurophysiology, 30625 Hannover, Germany.

Biochimica Et Biophysica Acta. Biomembranes
|November 22, 2023
PubMed

Insights

The α1 integrin cytoplasmic tail binds to phosphoinositides, particularly PI(3,4,5)P3, via its KIGFFKR motif. Mutations in this motif regulate α1β1 integrin activity, affecting cell adhesion and cytoskeleton dynamics.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Integrin α1β1 is a key adhesion receptor binding collagen and laminin.
  • It plays crucial roles in cell adhesion, cytoskeletal organization, and migration.
  • The α1 integrin cytoplasmic tail (α1CT) has a unique structure with six lysine residues.

Purpose of the Study:

  • To investigate the interaction between the α1CT and phosphoinositides.
  • To identify the specific motif and residues involved in this interaction.
  • To elucidate the role of this interaction in regulating α1β1 integrin activity.

Main Methods:

  • Peptide-lipid interaction studies using the α1CT and phosphoinositides.
  • Site-directed mutagenesis of the KIGFFKR motif within the α1CT.
  • Analysis of cell adhesion, F-actin cytoskeleton formation, and integrin activation.
  • Assessment of focal adhesion formation and kinase phosphorylation (FAK, AKT).

Main Results:

  • The α1CT directly associates with phosphoinositides, notably phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3).
  • This ionic interaction is mediated by the KIGFFKR motif, particularly lysine 1171.
  • Mutations in the KIGFFKR motif enhanced integrin-specific adhesion and F-actin assembly.
  • Mutation of lysine 1171 increased cell surface α1β1 integrin levels and focal adhesion kinase phosphorylation, while decreasing AKT phosphorylation.

Conclusions:

  • The KIGFFKR motif, especially lysine 1171, is critical for the dynamic regulation of α1β1 integrin.
  • The interaction of α1CT with phosphoinositides contributes to regulating integrin activity.
  • This interaction influences cell adhesion, cytoskeletal organization, and signaling pathways.

Keywords:
AKTCytoplasmic tailFAKPI(3,4,5)P(3)PI(4,5)P(2)α(1)β(1) integrin

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