Collagen induces activation of DDR1 through lateral dimer association and phosphorylation between dimers

Area of Science:

• Cellular signaling
• Molecular biology
• Biochemistry

Background:

• Discoidin domain receptor 1 (DDR1) is a collagen-binding receptor tyrosine kinase implicated in various human diseases.
• The precise molecular mechanism governing DDR1 activation remains incompletely understood.
• DDR1's role as a drug target necessitates a clear understanding of its activation pathways.

Purpose of the Study:

• To elucidate the molecular mechanism of discoidin domain receptor 1 (DDR1) activation by collagen.
• To investigate the roles of receptor dimerization, kinase activity, and specific domains in DDR1 signaling.
• To provide a mechanistic basis for targeting DDR1 in disease.

Main Methods:

• Co-expression of functional and signaling-incompetent DDR1 mutants.
• Utilizing enforced covalent DDR1 dimerization to study trans-phosphorylation.
• Site-directed mutagenesis to probe the function of DDR1 domains (ectodomain, transmembrane domain).
• Analysis of DDR1 recruitment into signaling clusters.

Main Results:

• Collagen binding induces phosphorylation of signaling-incompetent DDR1 ('receiver') by functional DDR1 ('donor').
• Trans-phosphorylation of DDR1 dimers requires the kinase activity of the donor receptor but not the receiver.
• The transmembrane domain, but not the ectodomain, is essential for trans-phosphorylation.
• Mutant DDR1 unable to bind collagen is still recruited into DDR1 signaling clusters.

Conclusions:

• Collagen binding promotes lateral association of DDR1 dimers.
• Activation involves trans-phosphorylation between DDR1 dimers, mediated by the kinase activity of one dimer partner.
• The transmembrane domain plays a critical role in facilitating DDR1 activation.
• These findings reveal a novel mechanism for DDR1 activation, crucial for its role in disease.