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β1 integrins with individually disrupted cytoplasmic NPxY motifs are embryonic lethal but partially active in the

Alexander Meves1, Christopher Stremmel2, Ralph T Böttcher2

  • 1Department of Dermatology, Mayo Clinic, Rochester, Minnesota, USA.

The Journal of Investigative Dermatology
|May 25, 2013
PubMed

Insights

Beta1 integrin adhesion relies on talins and kindlins binding to specific tail motifs. Mutations blocking these interactions cause embryonic lethality and skin defects, revealing distinct roles in different cell types.

Area of Science:

  • Cell Biology
  • Integrin Signaling
  • Developmental Biology

Background:

  • Beta1 integrin (β1 integrin) is crucial for cell adhesion, migration, and tissue development.
  • Talin and kindlin proteins are known to bind to specific NPxY motifs in the β1 integrin cytoplasmic tail, mediating adhesion.
  • The precise roles of individual NPxY motifs and their associated binding partners in β1 integrin function remain incompletely understood.

Purpose of the Study:

  • To investigate the functional significance of the membrane-proximal and membrane-distal NPxY motifs in the β1 integrin cytoplasmic tail.
  • To determine the specific roles of talin and kindlin binding to these motifs in β1 integrin-mediated adhesion and cellular processes.
  • To compare the effects of disrupting these binding sites in different cellular contexts, including embryonic development and epidermal keratinocytes.

Main Methods:

  • Generation of germline mutant mice with specific tyrosine-to-alanine substitutions (β1 Y783A and β1 Y795A) in the β1 integrin cytoplasmic tail.
  • Analysis of peri-implantation lethality and embryonic development in mutant mice.
  • Assessment of skin and hair follicle phenotypes in mice expressing mutant β1 integrin in the epidermis.
  • In vitro studies evaluating cell adhesion, spreading, and migration in cultured cells expressing mutant β1 integrin variants.

Main Results:

  • Specific substitutions (β1 Y783A or β1 Y795A) selectively blocked talin or kindlin binding, respectively.
  • Mutations led to β1 null-like peri-implantation lethality, indicating essential roles during early embryogenesis.
  • Epidermal expression of single mutations caused milder skin and hair phenotypes compared to β1 integrin deletion or double mutations.
  • In vitro, β1 Y783A impaired adhesion, spreading, and migration more severely than β1 Y795A, despite reduced surface levels and stability of β1 Y795A.

Conclusions:

  • Talin and kindlin binding to distinct NPxY motifs in the β1 integrin tail differentially regulate adhesion.
  • The functional requirements for β1 integrin adhesion mediated by talins and kindlins differ between embryonic cells and keratinocytes.
  • Individual NPxY motifs contribute independently to β1 integrin function in keratinocytes, highlighting context-dependent mechanisms.

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