6y23 Citations

Two-step release of kinase autoinhibition in discoidin domain receptor 1.

Proc Natl Acad Sci U S A 117 22051-22060 (2020)
Cited: 5 times
EuropePMC logo PMID: 32839343

Abstract

Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase with important functions in organogenesis and tissue homeostasis. Aberrant DDR1 activity contributes to the progression of human diseases, including fibrosis and cancer. How DDR1 activity is regulated is poorly understood. We investigated the function of the long intracellular juxtamembrane (JM) region of human DDR1 and found that the kinase-proximal segment, JM4, is an important regulator of kinase activity. Crystal structure analysis revealed that JM4 forms a hairpin that penetrates the kinase active site, reinforcing autoinhibition by the activation loop. Using in vitro enzymology with soluble kinase constructs, we established that release from autoinhibition occurs in two distinct steps: rapid autophosphorylation of the JM4 tyrosines, Tyr569 and Tyr586, followed by slower autophosphorylation of activation loop tyrosines. Mutation of JM4 tyrosines abolished collagen-induced DDR1 activation in cells. The insights may be used to develop allosteric, DDR1-specific, kinase inhibitors.

Articles - 6y23 mentioned but not cited (1)

  1. Structure of LRRK1 and mechanisms of autoinhibition and activation. Reimer JM, Dickey AM, Lin YX, Abrisch RG, Mathea S, Chatterjee D, Fay EJ, Knapp S, Daugherty MD, Reck-Peterson SL, Leschziner AE. Nat Struct Mol Biol 30 1735-1745 (2023)


Reviews citing this publication (2)

  1. Extracellular matrix-induced signaling pathways in mesenchymal stem/stromal cells. Novoseletskaya ES, Evdokimov PV, Efimenko AY. Cell Commun Signal 21 244 (2023)
  2. Genetic and pharmacological tools to study the role of discoidin domain receptors in kidney disease. Borza CM, Bolas G, Pozzi A. Front Pharmacol 13 1001122 (2022)

Articles citing this publication (2)