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Discoidin domain receptor 1 is activated independently of beta(1) integrin

W Vogel1, C Brakebusch, R Fässler

  • 1Programme in Molecular Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. W.Vogel@em.uni-frankfurt.de

The Journal of Biological Chemistry
|February 22, 2000
PubMed

Insights

Discoidin domain receptor (DDR) tyrosine kinases are activated by collagen. This study shows DDR1 signaling is independent of integrins and essential for myoblast differentiation, distinct from epidermal growth factor receptor activation.

Area of Science:

  • Cellular signaling and kinase activity
  • Integrin and receptor tyrosine kinase interactions
  • Muscle differentiation and development

Background:

  • Mammalian discoidin domain receptor (DDR) tyrosine kinases, DDR1 and DDR2, bind to various collagen types.
  • The precise mechanism of collagen-induced DDR activation, including potential coreceptors like integrins, remains unclear.
  • The role of collagen-binding integrins (alpha(1)beta(1) or alpha(2)beta(1)) in DDR activation is undefined.

Purpose of the Study:

  • To investigate whether DDR1 signaling is distinct from integrin activation.
  • To determine the role of DDR1 enzymatic activity in collagen-induced receptor phosphorylation.
  • To elucidate the function of DDR1 in cellular differentiation, specifically in myoblasts.

Main Methods:

  • Utilized dominant-negative DDR1 mutants and recombinant extracellular domains to block DDR1 activity.
  • Assessed DDR1 activation in cells expressing both DDR1 and epidermal growth factor (EGF) receptor upon EGF stimulation.
  • Examined DDR1 activation in cells with blocked alpha(2)beta(1) integrin or beta(1) integrin gene deletion.
  • Overexpressed dominant-negative DDR1 in C2C12 myoblasts to study effects on differentiation.

Main Results:

  • Enzymatic activity of DDR1 is essential for its tyrosine phosphorylation, which can be inhibited by dominant-negative mutants or extracellular domain preparations.
  • DDR1 signaling is independent of the epidermal growth factor (EGF) receptor, as EGF stimulation did not activate DDR1.
  • Full DDR1 activation occurred after collagen stimulation even when alpha(2)beta(1) integrin was blocked or beta(1) integrin was deleted.
  • Overexpression of dominant-negative DDR1 in C2C12 myoblasts inhibited cellular differentiation and myofiber formation.

Conclusions:

  • DDR1 signaling is distinct from integrin activation and EGF receptor signaling.
  • DDR1 kinase activity is crucial for its autophosphorylation upon collagen binding.
  • DDR1 plays a critical role in myoblast differentiation and myofiber formation.

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