Discoidin Domain Receptors (DDR1 and DDR2): Activators And Inhibitors

 

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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795932/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795932/

 

DDR Basics

The Discoidin Domain Receptor (DDR) family are collagen receptors. R

DDR1 and DDR2 are tyrosine kinase receptors in the extracellular matrix that mediate mediate cell aggregation.

Both receptors are activated upon binding to collagen - DDR1 and DDR2 are unique in that they exhibit remarkably delayed and sustained receptor phosphorylation upon binding to collagen. R

DDR2 can only be activated by fibrillar collagen, particularly types I and III, DDR1 is mostly activated by type I and IV collagens. R

DDR In The Body

Loss of DDR1 or DDR2 causes major dysfunctions in:

  • Cancer R
  • Cardiovascular Health R
  • Inflammatory Responses R
  • MuscleSkeletal Development R
  • Reproduction R

DDR1 And DDR2 In Cancer

DDR1 As A Positive Regulator R

Proliferation/survival

  • glioma (DDR1a but not DDR1b) 
  • pancreatic adenocarcinoma
  • colon carcinoma
  • osteosarcoma
  • breast cancer
  • Hodgkin lymphoma

EMT

  • hepatoma
  • non-small cell lung carcinoma
  • colorectal cancer
  • pancreatic adenocarcinoma

Migration

  • glioma
  • hepatocellular carcinoma
  • non-small cell lung carcinoma
  • pancreatic cancer
  • colorectal cancer
  • breast cancer

Invasion

  • glioma
  • hepatocellular carcinoma
  • oral squamous cell carcinoma
  • colorectal cancer
  • non-small cell lung carcinoma
  • hepatoblastoma
  • breast cancer
  • prostate cancer
  • pituitary adenoma

DDR1 As A Negative Regulator R

Proliferation/survival

  • breast cancer

EMT

  • breast cancer

Migration

  • breast cancer

DDR2 As A Positive Regulator R

Proliferation/survival

  • squamous cell lung cancer
  • osteosarcoma
  • squamous cell lung cancer
  • melanoma
  • hepatoma
  • colon carcinoma

EMT

  • lung carcinoma
  • breast cancer

Migration

  • melanoma
  • hepatoma
  • colon carcinoma
  • prostate cancer
  • lung carcinoma
  • nasopharyngeal carcinoma (isolated cells)

Invasion

  • prostate cancer
  • squamous cell lung cancer
  • breast cancer

DDR2 As A Negative Regulator R

Proliferation/survival

  • melanoma
  • fibrosarcoma
  • squamous cell lung cancer

Migration

  • colon carcinoma (Murine)

What Increases DDR1 And DDR2?

DDR1

DDR2

  • Hypoxia R

DDR1 And DDR2 Inhibitors

DDR1 R

  • Dasatinib
  • DDR1-IN-1
  • DDR1-IN-2
  • Imatinib
  • Nilotinib
  • LCB 03-0110
  • Ponatinib
  • 2a
  • 4a
  • 4b
  • 7rh
  • 7rj

DDR2 R

  • Actinomycin D
  • Dasatinib
  • DDR1-IN-1
  • DDR1-IN-2
  • Imatinib
  • Nilotinib
  • LCB 03-0110
  • Ponatinib
  • 2a
  • 4a
  • 4b
  • 7rh
  • 7rj

Mechanism Of Action

Simple DDR1:

  • Increases COX2 R
  • Increases MMP-2 R
  • Increases MMP-9 R
  • Increases NOTCH 1 R
  • Reduces TGFb1 R

Simple DDR2:

  • Increases COX2 R
  • Increases ERK1/2 R
  • Increases MMP-2 R
  • Increases MMP-9 R
  • Increases SNAIL1 R
  • Increases TGFb1 R

Advanced:

  • Unlike DDR2, five isoforms of DDR1 (DDR1a, b, c, d, and e) have been described as they exhibit differences in the extent of glycosylation, phosphorylation, protein interactions, expression patterns, and functions. R
  • Binds to Shc1, Nck2, SHP-2, Cdc42, NF-κB, ERK1/2-MAPK, (AP)-1, STAT R

Genetics

DDR2

I638F

  • Mutation known as I638F, has been shown to promote resistance to inhibitors of DDR2 kinase function R