Spatial localisation of Discoidin Domain Receptor 2 (DDR2) signalling is dependent on its collagen binding and kinase activity

Abstract

Discoidin Domain Receptor 2 (DDR2) is a collagen-binding receptor tyrosine kinase that initiates delayed and sustained tyrosine phosphorylation signalling. To understand the molecular basis of this unique phosphorylation profile, here we utilise fluorescence microscopy to map the spatiotemporal localisation of DDR2 and tyrosine phosphorylated proteins upon stimulation with collagen. We show that cellular phosphorylated proteins are localised to the interface where DDR2 is in contact with collagen and not in the early endosomes or lysosomes. We find that DDR2 localisation is independent of integrin activation and the key DDR2 signalling effector SHC1. Structure-function analysis reveals that DDR2 mutants defective for collagen binding or kinase activity are unable to localise to the cell surface, demonstrating for the first time that both collagen binding and kinase functions are required for spatial localisation of DDR2. This study provides new insights into the underlying structural features that control DDR2 activation in space and time.

Clustering, Spatial Distribution, and Phosphorylation of Discoidin Domain Receptors 1 and 2 in Response to Soluble Collagen I

“…Recent studies have reported the co-localization of total and pDDRs in cells with collagen [20,21,36]. Our results expand these observations by showing that higher-order assembly of DDRs into receptor clusters and/or filamentous structures may associate with different morphological states of collagen.…”

Collagen synthesis in the skin, its functional and structural features

“…Это может зависеть от разных факторов, как внешних, так и внутренних [3,4]. К таким факторам относятся и генетические особенности, в том числе обмена коллагена [5,6]. Знания особенностей обмена коллагена в коже могут помочь в выборе наиболее эффективных процедур во врачебной косметологии и сделать шаг в сторону персонализированной и предиктивной медицины в рассматриваемой области медицинской науки [7].…”