DDR1 - discoidin domain receptor tyrosine kinase 1 |Elisa - Clia - Antibody - Protein

Background

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase (RTK) that uniquely binds to collagens, distinguishing it from other RTKs that are primarily activated by growth factors or hormones. DDR1 is encoded by the DDR1 gene located on chromosome 6p21.3 in humans and is widely expressed across various tissues, including the kidneys, brain, lungs, and reproductive organs. DDR1 has critical roles in cell adhesion, proliferation, migration, and differentiation, primarily through its unique capacity to interact with the extracellular matrix (ECM), particularly collagens. As a collagen-binding receptor, DDR1 is involved in cellular responses to structural changes in the ECM, making it essential in tissue remodeling, wound healing, and organ development.

DDR1 has become increasingly significant in the context of cancer biology due to its involvement in cell adhesion and motility, which are critical for metastasis. It is also implicated in fibrotic diseases, where it contributes to tissue stiffness and fibrosis, and in immune response modulation. The discovery of DDR1 has broadened the understanding of RTKs, as it revealed a subset of kinases that function primarily through interactions with ECM proteins, underscoring its role in both physiological and pathological conditions.

Protein Structure

DDR1 has a distinct structure that allows it to recognize and bind collagen uniquely among RTKs. Its structural features include:

Extracellular Discoidin Domain:

• The extracellular discoidin (DS) domain, which gives the receptor its name, is primarily responsible for collagen binding. This domain shares homology with domains found in blood coagulation factors and cell adhesion proteins, and it binds specifically to collagens I, IV, and VI. This discoidin domain is unique because it allows DDR1 to recognize ECM components rather than soluble ligands.
• The DS domain of DDR1 undergoes conformational changes upon collagen binding, triggering receptor dimerization, a necessary step for autophosphorylation and activation.

Transmembrane Domain:

• The transmembrane domain of DDR1 anchors the receptor within the cell membrane and is essential for stabilizing the receptor structure within the lipid bilayer. This single-pass domain also plays a role in dimerization and the propagation of the activation signal from the extracellular collagen-binding event to the intracellular kinase domain.

Intracellular Tyrosine Kinase Domain:

• The intracellular kinase domain is responsible for signal transduction upon receptor activation. Unlike typical RTKs, which are activated within seconds to minutes, DDR1 activation by collagen binding is relatively slow, occurring over hours. This slower activation process is thought to allow for prolonged signaling and interaction with downstream signaling cascades.
• DDR1’s kinase domain undergoes autophosphorylation on several tyrosine residues, enabling the recruitment of downstream signaling molecules, including the Shc and PI3K pathways, which are critical in regulating cellular responses.

Juxtamembrane and Cytoplasmic Regions:

• DDR1 contains a juxtamembrane region that aids in regulating its kinase activity and can bind to intracellular proteins involved in signal transduction. It also contains tyrosine phosphorylation sites that act as docking sites for other signaling proteins, promoting complex formation and downstream pathway activation.

Classification and Subtypes

DDR1 is classified within the receptor tyrosine kinase (RTK) superfamily and the DDR subfamily, which includes two members: DDR1 and DDR2. These receptors are distinguished by their collagen-binding properties and slow activation kinetics. DDR1 exists in five isoforms, DDR1a to DDR1e, which arise from alternative splicing of the DDR1 gene:

DDR1a and DDR1b:

• These are the most widely expressed isoforms. DDR1a lacks a part of the cytoplasmic tail, while DDR1b is a full-length isoform and the most functionally active.

DDR1c, DDR1d, and DDR1e:

• These isoforms are less common and exhibit tissue-specific expression patterns. Each isoform shows slight differences in the cytoplasmic tail, which may influence their functional roles in different cellular environments.

Function and Biological Significance

DDR1 functions as a collagen receptor that regulates cell adhesion, migration, proliferation, and survival in response to ECM alterations. The primary biological roles of DDR1 include:

Collagen Interaction and ECM Remodeling:

• DDR1 is involved in ECM remodeling by mediating interactions between cells and collagens. Through collagen binding, DDR1 can influence cellular behavior in tissues where ECM structure changes, such as during development, wound healing, and fibrosis.
• Its activation by collagen promotes the reorganization of ECM components, which is vital for tissue integrity and cellular architecture.

Cell Adhesion and Migration:

• DDR1 plays a key role in cell adhesion by promoting stable adhesion to the ECM. It is also critical in cell migration, particularly in cancer cells, where it can enhance invasiveness and metastasis. DDR1 influences actin cytoskeletal organization, which is essential for cell movement.

Proliferation and Survival:

• Upon activation, DDR1 can promote cell proliferation and survival by initiating signaling pathways such as PI3K/AKT, which is essential for cell growth and anti-apoptotic signaling. DDR1’s function in survival signaling is particularly important in cancer cells, contributing to tumorigenesis and metastasis.

Role in Immune Modulation:

• DDR1 has been implicated in modulating immune cell behavior. Through its effects on cell adhesion, it may influence immune cell retention and migration in inflamed or fibrotic tissues. DDR1 signaling has been linked to macrophage activation and other immune responses, although this role is still being investigated.

Clinical Issues

DDR1’s involvement in cell adhesion, migration, and survival makes it relevant to a variety of diseases, including:

Cancer:

• DDR1 is overexpressed in several cancers, such as breast, lung, and ovarian cancer. In these malignancies, DDR1 promotes tumor cell invasion and metastasis by enhancing interactions with the ECM and facilitating cellular migration. Overexpression of DDR1 in tumors often correlates with poor prognosis and increased metastatic potential.
• Inhibiting DDR1 has shown promise in preclinical cancer models as it may limit tumor progression and metastatic spread. DDR1 inhibition is currently being explored as a therapeutic approach in targeting cancers with high DDR1 expression.

Fibrosis:

• DDR1 is implicated in fibrotic diseases, including liver, kidney, and lung fibrosis, where excessive collagen deposition and ECM remodeling lead to tissue stiffness and dysfunction. DDR1 activation in these tissues contributes to fibroblast activation and collagen synthesis, exacerbating fibrosis.
• Targeting DDR1 with inhibitors has demonstrated potential in reducing fibrosis in experimental models, suggesting that DDR1 inhibition could be a therapeutic strategy for treating fibrotic diseases.

Inflammatory Diseases:

• Due to its role in immune cell adhesion and ECM interaction, DDR1 may play a part in inflammatory diseases. Increased DDR1 expression in inflamed tissues can contribute to immune cell retention and activation, promoting chronic inflammation.

Potential as a Therapeutic Target:

• Given DDR1’s role in cancer and fibrosis, efforts are underway to develop DDR1 inhibitors. Selective inhibition of DDR1 could provide therapeutic benefits in diseases characterized by abnormal cell adhesion, migration, or ECM remodeling.

Summary

DDR1 is a unique receptor tyrosine kinase that binds to collagens in the ECM, setting it apart from other RTKs that bind to soluble ligands. Through its discoidin domain, DDR1 can interact with collagen types I, IV, and VI, initiating downstream signaling cascades that regulate cell adhesion, migration, proliferation, and survival. DDR1’s functions make it critical in tissue remodeling, wound healing, and immune response modulation, and it has significant roles in cancer and fibrotic diseases, where it promotes cell invasiveness, metastasis, and fibrosis.

The protein structure of DDR1, including its discoidin domain, transmembrane region, and intracellular kinase domain, enables its unique collagen-binding capacity and prolonged signaling. DDR1 exists in several isoforms, with DDR1b being the most functionally active. In cancer, DDR1 overexpression is linked to poor outcomes due to its role in enhancing tumor cell migration and invasion. In fibrotic diseases, DDR1 contributes to excessive collagen deposition and ECM remodeling, making it a potential therapeutic target.