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. 2022 Dec 1;17(3):1081–1088. doi: 10.1007/s12079-022-00714-x

A network map of discoidin domain receptor 1(DDR1)-mediated signaling in pathological conditions

Shobha Dagamajalu 1,✉,#, D A B Rex 2,✉,#, G P Suchitha 1, Akhila B Rai 1, Shreya Kumar 1, Shreya Joshi 1, Rajesh Raju 1,2, T S Keshava Prasad 1,✉
PMCID: PMC10409954  PMID: 36454444

Abstract

Abstract

Discoidin domain receptor 1 (DDR1) is one of the receptors that belong to a family of non-integrin collagen receptors. In common, DDR1 is predominantly found in epithelial and smooth muscle cells and its mainly involved in organogenesis during embryonic development. However, it’s also overexpressed in several pathological conditions, including cancer and inflammation. The DDR1 is reported in numerous cancers, including breast, prostate, pancreatic, bladder, lung, liver, pituitary, colorectal, skin, gastric, glioblastoma, and inflammation. DDR1 activates through the collagen I, IV, IGF-1/IGF1R, and IGF2/IR, regulating downstream signaling molecules such as MAPKs, PI3K/Akt, and NF-kB in diseases. Despite its biomedical importance, there is a lack of consolidated network map of the DDR1 signaling pathway, which prompted us for curation of literature data pertaining to the DDR1 system following the NetPath criteria. We present here the compiled pathway map comprises 39 activation/inhibition events, 17 catalysis events, 22 molecular associations, 65 gene regulation events, 35 types of protein expression, and two protein translocation events. The detailed DDR1 signaling pathway map is made freely accessible through the WikiPathways Database (https://www.wikipathways.org/index.php/ Pathway: https://www.wikipathways.org/index.php/Pathway:WP5288).

Graphical abstract

graphic file with name 12079_2022_714_Figa_HTML.jpg

Supplementary Information

The online version contains supplementary material available at 10.1007/s12079-022-00714-x.

Keywords: Cancer, Inflammation, Post-translational modifications, Protein–protein interactions, Signaling pathways, WikiPathways

Introduction

Discoidin domain receptor 1 (DDR1) belongs to a family of two non-integrin collagen receptors and shows tyrosine kinase activity (Shrivastava et al. 1997; Alves et al. 1995). It was first discovered by Johnson et al. in 1993 (Johnson et al. 1993). Collagens were identified as their physiological ligands (Shrivastava et al. 1997; Vogel et al. 1997). DDR1 is a widely studied receptor tyrosine kinase, predominantly expressed in normal epithelial cells. The DDR1 gene encodes on chromosome 6 (6p21.3) in humans and is composed of five exons, which undergo alternative splicing to form five different isoforms, i.e., from DDR1a to DDR1e (Dorison et al. 2017). DDR1 has been found in human bronchial epithelial cells, keratinocytes, colon epithelial cells, liver, cornea, and vascular smooth muscle cells, as well as developing neuroectoderm, mammary glands, brain, distal tubule, podocytes, and smooth muscle cells in mice (Gross et al. 2004; Vogel et al. 2006). DDR1 is activated in a variety of diseases to contribute to proliferation, inflammation, and fibrosis (Dorison et al. 2017).

The aberrant expression of DDR1 is associated with tumor progression in a variety of human cancers, including breast, lung, ovary, liver, gastric, and glioma (Weiner et al. 2000; Heinzelmann-Schwarz et al. 2004; Yamanaka et al. 2006; Park et al. 2007; Shen et al. 2010; Ambrogio et al. 2016; Jin et al. 2018). Several studies have reported that the role of DDR1 depends on the type and stage of the cancer; its overexpression promotes tumorigenesis and is associated with a poor prognosis (Valiathan et al. 2012; Borza and Pozzi 2014). DDR1 promotes the epithelial-mesenchymal transition in cancer cells and it can be used as a biomarker in renal cancer (Song et al. 2016). In addition, DDR1 plays a key role in pro-inflammatory and profibrotic processes in atherosclerosis (Franco et al. 2009; Dorison et al. 2017). It also plays a key role in the development of permanent pulmonary epithelial lesions in idiopathic pulmonary fibrosis (Chen et al. 2016).

DDR1 expression is related to the onset and progression of chronic kidney disease (Flamant et al. 2006). Its expression and activation in macrophages are required for efficient migration, indicating a role for DDR1 in mediating interstitial lesions caused by macrophage infiltration in the kidney (Guerrot et al. 2011). The collective evidence of several reports suggests that DDR1 is a potential therapeutic target, as it is involved in organ fibrosis and several cancers. DDR1 activation or overexpression induces major downstream signaling pathways such as PI3K/AKT/mTOR, MAPK1/3, MAPK14, MAPK8/9, NF-KB (Matada et al. 2021).

The inhibition of DDR1 receptor tyrosine kinase by inhibitors may provide an appealing strategy to treat the diseases. For example, several multi-target kinase inhibitors, including imatinib, dasatinib, and nilotinib, are being used to inhibit downstream signalings mediated by DDR1 (Kothiwale et al. 2015). In recent years, a panel of selective DDR1 kinase inhibitors such as DDR1‐IN‐1 and 7rh benzamide, which inhibit the kinase activity of DDR1 has been developed for the treatment of cancer including colorectal cancer cells and lung adenocarcinoma (Tao et al. 2019). The importance of DDR1 signaling in a variety of pathological conditions especially in different cancers and inflammation led us to create a DDR1 signaling pathway map. We created a signaling pathway map by literature mining to compile the molecular interactions between DDR1 and its ligand collagen. These have been systematically brought together through manual annotation of research articles available in the literature, allowing them to be represented as a single pathway map. The DDR1 signaling pathway map is made available through the WikiPathways database.

Methodology

We performed a literature search in PubMed for research articles pertaining to DDR1-mediated signaling to develop a consolidated pathway map of DDR1. The scientific articles were obtained from PubMed using the following search terms (“DDR1” OR “CAK” OR “CD167” OR “DDR” OR “EHGK2” OR “MCK10” OR “NEP” OR “NTRK4” OR “PTK3” OR “PTK3A” OR “RTK6” OR “TRKE” OR “discoidin domain receptor tyrosine kinase 1”) AND ("pathway" OR "signaling" OR "signalling"). The abstract of each research article was manually screened to select only articles relevant to DDR1-mediated signaling events. Signaling reactions were manually curated according to the previously published NetPath annotation criteria (Kandasamy et al. 2010). The curated reactions mediated by DDR1 signaling were categorized into five groups (1) molecular associations, (2) catalysis/post-translational modifications (PTMs), (3) protein-activation/inhibition, (4) protein/gene regulations, and (5) protein translocation between cell organelles. Additional information, including cell lines used in the experiment, experiment type, and the information about sites and residues of PTMs were also curated. Each molecular event described in the DDR1 signaling pathway was linked to the PubMed entry of the corresponding articles. Manual curation of signaling events was enabled using a manual curation software called PathBuilder (Kandasamy et al. 2009). PathVisio was used to depict and visualize the signaling pathway map (Kutmon et al. 2015).

Results and discussion

The query terms searched in PubMed retrieved a total of 105 articles, which are pertinent to DDR1 mediated signaling. The manual screening of these articles provided 56 articles, which had specific information on DDR1 mediated signaling. The manual annotation of these selected articles provided 39 activation/inhibition events, 16 enzyme catalysis, 35 protein expression events, 65 gene regulation events, 22 molecular association and 2 translocation events (Supplementary Data S1). These events were compiled into a comprehensive pathway map of DDR1 signaling and made freely accessible through WikiPathways with the ID (Fig. 1).

Fig. 1.

Fig. 1

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Schematic representation of DDR1-mediated signaling pathway. Schematic representation of DDR1 induced signaling reactions. The signaling pathway map represents molecules involved in ligand-receptor interactions and DDR1 activated downstream molecular events including molecular association, enzyme catalysis, translocation, and gene regulation events. Information regarding the post-translational modification site and the residue is also shown in the pathway

A brief summary of DDR1 – mediated signaling map

DDR1 is involved in many physiological and pathological conditions such as proliferation, inflammation and fibrosis (Dorison and Chantziantoniou 2018). The different expression levels of DDR1 and its complex effects in tumor progression has been widely reported in several types of human cancer, including breast cancer, renal clear cell carcinoma, non-small cell lung carcinoma, esophageal cancer, astrocytoma, prostate cancer, hepatocellular carcinoma and Hodgkin's lymphoma (Nemoto et al. 1997; Willenbrock et al. 2006; Shimada et al. 2008; Shen et al. 2010; Yang et al. 2010; Quan et al. 2011; Nakada et al. 2013; Toy et al. 2015; Song et al. 2016).

Breast cancer

In breast cancer cells, collagen I induce the phosphorylation of DDR1 at Tyr 484 and 740, interacting with NCK2 and PTPN11, respectively. This report demonstrated that NCK2 and PTPN11, as direct interaction partners of DDR1, play a physiological role in mammary gland development and during tumor invasion (Koo et al. 2006). Hansen et al. (2006) have reported that the phosphorylation of PPP1R1B (Dopamine and cAMP-regulated neuronal phosphoprotein, molecular mass 32 kDa, DARPP-32) at Thr 34 by the activation of DDR1 through collagen I reduces the migration of breast tumor cells (Hansen et al. 2006). The collagen IV-induced activation of DDR1 enhanced the PTGS2 expression, improving chemoresistance by activating the NF-kB pathway through IKBKB and IKBKG activation in breast cancer cells (Das et al. 2006). Collagen IV induces cell migration through the DDR1 and CD9-dependent pathway in MDA-MB-231 cancer cells (Castro-Sanchez et al. 2010). Collagen I induces DDR1 phosphorylation at Tyr 792 and attenuated mRNA expression of cell dependent kinases (CDK) CDK1, CDK6, CDKN1A, and KIAA0101, which enhanced BIK (BCL2 Interacting Killer) expression in cell cycle arrest and apoptosis in MCF-7 cells (Assent et al. 2015). The stimulation with IGF-1, induce the DDR1 overexpression and association with IGF-1R, which phosphorylates DDR1 at the Tyr 792 and activates AKT1 and MAPK1/3 pathways, which promotes the cancer progression in MCF-7 cells (Malaguarnera et al. 2015). The study in MCF-1 cells, IGF-1 stimulation induces DDR1 overexpression that activates IGF1R, PIK3CA/AKT1, and MAPK1/3 pathways that enhance cell growth and migration. AKT1 attenuated the expression of miR-199a-5p, which in turn leads to the upregulation of DDR1. This result demonstrated that the AKT / miR-199a-5p/DDR1 pathway plays a role in cell migration and proliferation in response to IGF-I (Mata et al. 2016). Vella et al (2017) have reported that insulin and IGF-2 activates insulin receptor (IR), which associate with DDR1 and induces the activation of the MAPK1/3 and AKT1 pathways, thereby regulating the upregulation of HMGA1, SP1, IR, and downregulation of TP53 which are involved in cancer progression and metastasis in breast cancer cells. Due to the overexpression of DDR1, which upregulates IR and downregulates p53 in breast cancer cells (Vella et al. 2017).

Prostate cancer

The overexpression of prostate cancer antigen (PCA)-1 contributes in the inhibition of apoptosis and invasiveness of human prostate cancer cells through the expression of BCL2L1 and MMP9 mediated by DDR1 (Shimada et al. 2008). Azizi et al (2019) have reported that collagen I induces autophosphorylation of DDR1 in prostate cancer cells LNcap‐FGC and DU145, which in turn induces the phosphorylation of the proteins such as PYK2 and MKK7 (MAP2K7) and promotes epithelial-to-mesenchymal transition (EMT) through enhanced expression of CDH2 and vimentin and induces migration by the attenuated expression of CDH1 (Azizi et al. 2019). In agreement with this, Zhao et al (2021) have reported that the overexpression of DDR1 promotes the EMT phenotype by increasing the expression of vimentin and fibronectin and down-regulation of CDH1 via the MAPK1/3 pathway in prostate cancer (Zhao et al. 2021).

Pancreatic cancer

In pancreatic cancer cells, phosphorylation of DDR1 at Tyr residue by collagen 1 induces the formation of a complex with PTK2B and BCAR1 and activation of RAP1GAP, MAP3K11, MAP2K7, MAPK8, JUN, and up-regulation of CDH2 protein, which are involved in tumor growth, invasion, and metastasis (Shintani et al. 2008). Huang et al (2016) reported that collagen I stimulates DDR1 phosphorylation at Tyr 513 and induces the up-regulation of CDH2 through the interaction between SHC1, phosphorylated PTK2B (Tyr 402), and promoted EMT in pancreatic cancer cells (Huang et al. 2016). The study by Aguilera et al (2017) reported that collagen I mediated activation of DDR1 induces the activation of SRC (Tyr 416), PEAK1 (Tyr 665), and PTK2B (Tyr 402), which are potentially responsible for collagen-induced chemoresistance and tumor progression in pancreatic cancer cells (Aguilera et al. 2017).

Bladder cancer

The overexpression of collagen IV and DDR1 in bladder cancer cells enhances cell motility and invasion and facilitates EMT-inducing transcription factors through enhanced expression of MMP2, ZEB1, and SLUG (Xie et al. 2020). DDR1 is phosphorylated by IGF1 and IGF2 at Tyr 792, forms a complex between PTK2B, MYH9, and IGFIR and induces cancer cell motility by regulating actin skeleton dynamics in bladder cancer cells (Buraschi et al. 2020).

Lung cancer

In Non-small-cell lung cancer cells (NSCLC), the overexpression of TM4SF1 interacts with DDR1 and promotes cancer proliferation, invasion and chemoresistance by activating AKT / MTOR pathway (Ye et al. 2019). Collagen I induces the upregulation of DDR1 and promotes cell invasion via EMT by enhancing the expression of CDH2, VIM, and MMP9 and attenuated CDH1 in A549 cells (Miao et al. 2013).

Other cancers

The overexpression of DDR1 by collagen I in pituitary adenocarcinoma and hepatocellular carcinoma cells mediates cell invasion by increasing the expression of MMP-2 and MMP-9 (Park et al. 2007; Yoshida and Teramoto 2007a, b). DDR1 phosphorylation by collagen I induces the activation of AKT1 and MAPK1/3 pathways and regulates the expression of ICAM1, VCAM1, MKI67, MMP9, and promotes invasion in human melanoma, colon carcinoma, and hepatoma cells (Romayor et al. 2020). In colorectal cancer cells, collagen I-mediated DDR1 phosphorylation at Tyr 792 induces the phosphorylation of BCR at Tyr 177, which disrupts the BCR / CTNNB1 interaction, resulting in an increased CTNNB1 nuclear activity that leads to the expression of target genes including MYC, FRA1, and JUN necessary for cell invasion (Jeitany et al. 2018). In skin cancer cells, DDR1 forms a complex with F2RL2 and PARD6A, which controls the localization of RhoE to cell–cell contacts, where it suppresses actinomyosin contractility, and promotes collective cell migration (Hidalgo-Carcedo et al. 2011). Hur et al (2017) have reported that collagen I/DDR1 signaling promotes tumor aggressiveness and EMT in gastric cancer by the phosphorylation of DDR1 at Tyr 792, PYK2 in Tyr 402 and reduced expression of CDH1(Hur et al. 2017). DDR1 overexpression increases IR protein and gene expression, which in turn increases the phosphorylation of AKT1 at Ser 473 and MAPK1/3 in Thr 202/Tyr 204, which regulates cell differentiation through the IGF-2 / IR-1 autocrine signaling loop in anaplastic thyroid cancer cells (Vella et al. 2019). In glioblastoma, collagen I stimulates DDR1 phosphorylation and forms a complex with YWHAB, BECN1, and AKT1 which mediates AKT1 and MTOR signaling to regulate the sensitivity of autophagy-associated therapy (Vehlow et al. 2019).

Inflammation and fibrosis

Collagen I phosphorylates DDR1 at Tyr 513 and Tyr 792 and forms a DDR1/MYH9/ACTB complex that interacts with SEC61B in the endoplasmic reticulum (ER). This interaction promotes nuclear translocation of DDR1 and its association with chromatin where they interacts with transcription factors MYH9 and ACTB and enhances the transcription of collagen IV and promotes fibrosis in the proximal tubules of the injured human and mouse kidneys (Chiusa et al. 2019). Collagen I/DDR1 interaction in human macrophages enhances the production of IL-1B, CXCL8, CCL3, and CCL2 via activation of MAPK14, and NFKB pathways, providing a novel mechanism by which macrophages produce and release large amounts of these chemokines in a tissue microenvironment in the course of inflammatory responses (Matsuyama et al. 2004). Collagen I stimulates DDR1 activation and induces NO production through NOS2 expression, and activation of RELA, MAPK14, and MAPK 8/9 pathways induces an increased inflammatory response in J774 murine macrophages (Kim et al. 2007). Seo et al (2008) reported that collagen promotes inflammation in the brain by stimulating microglial brain cells through the activation of DDR1, which induces upregulation of NOS2, PTGS2, CD40, and MMP9 via RELA, MAPK14, and MAPK 8/9 pathways perpetuating neuroinflammation (Seo et al. 2008). DDR1 stimulated by COL1A1 and COL8A1 phosphorylates DDR1 and stimulates the expression of MMP2 and MMP9 in rat injured artery smooth muscle cells, which induces proliferation, migration and invasion during arterial wound repair (Hou et al. 2001).

Conclusions

The DDR1-mediated signaling is involved in various cellular processes including cell proliferation, invasion, migration, differentiation, and cytokine expression. It is highly expressed in malignancies compared to normal cells. This suggested that DDR1 might be a potential target for cancer management. Recently, a panel of selective DDR1 kinase inhibitors has been developed, such as DDR1IN1 and 7rh benzamide, which inhibit DDR1 kinase activity for treating diseases including cancer. Therefore, the accessibility of DDR1-mediated signaling in the public resource will help biomedicine researchers to understand the role of DDR1 in the progression of diseases. We believe that this resource will provide a platform to the scientific community to identify novel therapeutic drug targets for cancer associated with DDR1 signaling.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 104 kb) (104.3KB, xlsx)

Acknowledgements

We thank Karnataka Biotechnology and Information Technology Services (KBITS), Government of Karnataka, for the support to the Center for Systems Biology and Molecular Medicine at Yenepoya (Deemed to be University) under the Biotechnology Skill Enhancement Programme in Multiomics Technology (BiSEP GO ITD 02 MDA 2017).

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Shobha Dagamajalu and D. A. B. Rex have Contributed equally to this work.

Contributor Information

Shobha Dagamajalu, Email: shobha_d@yenepoya.edu.in.

D. A. B. Rex, Email: rexprem@yenepoya.edu.in

G. P. Suchitha, Email: suchithajrf@yenepoya.edu.in

Akhila B. Rai, Email: akhilajrf@yenepoya.edu.in

Shreya Kumar, Email: shreyasunilkumar911@gmail.com.

Shreya Joshi, Email: shreyaj1400@gmail.com.

Rajesh Raju, Email: rajeshraju@yenepoya.edu.in.

T. S. Keshava Prasad, Email: keshav@yenepoya.edu.in.

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