Recent Advances in the Role of Discoidin Domain Receptor Tyrosine Kinase 1 and Discoidin Domain Receptor Tyrosine Kinase 2 in Breast and Ovarian Cancer.
Frontiers in cell and developmental biology
Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-β, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.
10.3389/fcell.2021.747314
Collagen and Discoidin Domain Receptor 1 Partnership: A Multifaceted Role in the Regulation of Breast Carcinoma Cell Phenotype.
Saby Charles,Maquoi Erik,Saltel Frédéric,Morjani Hamid
Frontiers in cell and developmental biology
Type I collagen, the major components of breast interstitial stroma, is able to regulate breast carcinoma cell behavior. Discoidin domain receptor 1 (DDR1) is a type I collagen receptor playing a key role in this process. In fact, collagen/DDR1 axis is able to trigger the downregulation of cell proliferation and the activation of BIK-mediated apoptosis pathway. The aim of this review is to discuss the role of two important factors that regulate these processes. The first factor is the level of DDR1 expression. DDR1 is highly expressed in epithelial-like breast carcinoma cells, but poorly in basal-like ones. Moreover, DDR1 undergoes cleavage by MT1-MMP, which is highly expressed in basal-like breast carcinoma cells. The second factor is type I collagen remodeling since DDR1 activation depends on its fibrillar organization. Collagen remodeling is involved in the regulation of cell proliferation and apoptosis through age- and proteolysis-related modifications.
10.3389/fcell.2021.808625
Discoidin domain receptor 1: a new class of receptor regulating leukocyte-collagen interaction.
Yoshimura Teizo,Matsuyama Wataru,Kamohara Hidenobu
Immunologic research
Previous studies demonstrated that type I collagen, a major component of the extracellular matrix, could influence the differentiation and function of leukocytes; however, it is not clear whether those effects of collagen were based on its interaction with the classic collagen receptors, alpha1beta1 and alpha2beta1 integrins. We recently detected significant upregulation of discoidin domain receptor 1 (DDR1), a new class of collagen receptor, in human leukocytes, including neutrophils, monocytes, and lymphocytes, in vitro, leading to the hypothesis that the leukocyte-activating effects of collagen might be owing to its interaction with DDR1. In this review, we summarize our recent findings demonstrating that DDR1-collagen interaction facilitates the adhesion, migration, differentiation/maturation, and cytokine/chemokine production of leukocytes. We also describe the intracellular signaling pathways activated by DDR1 interaction with collagen.
10.1385/IR:31:3:219
The Yin and Yang of Discoidin Domain Receptors (DDRs): Implications in Tumor Growth and Metastasis Development.
Majo Sandra,Auguste Patrick
Cancers
The tumor microenvironment is a complex structure composed of the extracellular matrix (ECM) and nontumoral cells (notably cancer-associated fibroblasts (CAFs) and immune cells). Collagens are the main components of the ECM and they are extensively remodeled during tumor progression. Some collagens are ligands for the discoidin domain receptor tyrosine kinases, DDR1 and DDR2. DDRs are involved in different stages of tumor development and metastasis formation. In this review, we present the different roles of DDRs in these processes and discuss controversial findings. We conclude by describing emerging DDR inhibitory strategies, which could be used as new alternatives for the treatment of patients.
10.3390/cancers13071725
Receptor tyrosine kinases: principles and functions in glioma invasion.
Nakada Mitsutoshi,Kita Daisuke,Teng Lei,Pyko Ilya V,Watanabe Takuya,Hayashi Yutaka,Hamada Jun-ichiro
Advances in experimental medicine and biology
Protein tyrosine kinases are enzymes that are capable of adding a phosphate group to specific tyrosines on target proteins. A receptor tyrosine kinase (RTK) is a tyrosine kinase located at the cellular membrane and is activated by binding of a ligand via its extracellular domain. Protein phosphorylation by kinases is an important mechanism for communicating signals within a cell and regulating cellular activity; furthermore, this mechanism functions as an "on" or "off" switch in many cellular functions. Ninety unique tyrosine kinase genes, including 58 RTKs, were identified in the human genome; the products of these genes regulate cellular proliferation, survival, differentiation, function, and motility. Tyrosine kinases play a critical role in the development and progression of many types of cancer, in addition to their roles as key regulators of normal cellular processes. Recent studies have revealed that RTKs such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Met, Tie, Axl, discoidin domain receptor 1 (DDR1), and erythropoietin-producing human hepatocellular carcinoma (Eph) play a major role in glioma invasion. Herein, we summarize recent advances in understanding the role of RTKs in glioma pathobiology, especially the invasive phenotype, and present the perspective that RTKs are a potential target of glioma therapy.
10.1007/978-94-007-4719-7_8
[Research Progress of Discoidin Domain Receptor 1 in Breast Cancer and Other Malignant Tumors].
Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae
Discoidin domain receptor 1(DDR1)is a critical member of the receptor tyrosine kinase family.It may be related to tumor invasion and metastasis,and the abnormal activation of DDR1 can lead to the occurrence and development of malignant tumors,inflammation,and fibrosis.DDR1 are involved in cell adhesion,migration,proliferation,secretion of cytokines,and remodeling of extracellular matrix,thus playing a critical role in various pathophysiological processes of the human body.In this review,we demonstrate the research progress of DDR1 in breast cancer and other malignant tumors,in order to provide a new theoretical basis for the prevention and treatment of breast cancer and other tumors.
10.3881/j.issn.1000-503X.13315
A putative role for Discoidin Domain Receptor 1 in cancer chemoresistance.
Ambrogio Chiara,Darbo Elodie,Lee Sam W,Santamaría David
Cell adhesion & migration
The Discoidin Domain Receptor 1 (DDR1) receptor tyrosine kinase performs pleiotropic functions in the control of cell adhesion, proliferation, survival, migration, and invasion. Aberrant DDR1 function as a consequence of either mutations or increased expression has been associated with various human diseases including cancer. Pharmacological inhibition of DDR1 results in significant therapeutic benefit in several pre-clinical cancer models. Here, we discuss the potential implication of DDR1-dependent pro-survival functions in the development of cancer resistance to chemotherapeutic regimens and speculate on the molecular mechanisms that might mediate such important feature.
10.1080/19336918.2018.1445954
KIBRA Team Up with Partners to Promote Breast Cancer Metastasis.
Singh Garima,Mishra Sarthak,Chander Harish
Pathology oncology research : POR
Among women, breast cancer is the most frequently diagnosed cancer. Most of the breast cancers represent metastasis to distant organs at the time of diagnosis and accounts for the majority of deaths. Metastasis is characterized by many genetic aberrations including mutations, overexpression of oncogenes etc. KIBRA (KIdney/BRAin protein), a scaffolding protein is recently described as an important player in the process of invasion and metastasis. The Kidney/BRAin protein through its different domains interacts with various proteins to couple cytoskeleton arrangement, cell polarity and migration. N terminal and C terminal of the protein contains the WW, Internal C & putative class III PDZ domain that interacts with DDR1, DLC1 & PKCζ. These protein-protein interactions equip the breast cancer cells to invade and metastasize. Here, we discuss a comprehensive knowledge about the KIBRA protein, its domains and the interacting partners involved in metastasis of breast cancer.
10.1007/s12253-019-00660-x
Multitasking discoidin domain receptors are involved in several and specific hallmarks of cancer.
Cell adhesion & migration
Discoidin domain receptors, DDR1 and DDR2, are two members of collagen receptor family that belong to tyrosine kinase receptor subgroup. Unlike other matrix receptor-like integrins, these collagen receptors have not been extensively studied. However, more and more studies are focusing on their involvement in cancer. These two receptors are present in several subcellular localizations such as intercellular junction or along type I collagen fibers. Consequently, they are involved in multiple cellular functions, for instance, cell cohesion, proliferation, adhesion, migration and invasion. Furthermore, various signaling pathways are associated with these multiple functions. In this review, we highlight and characterize hallmarks of cancer in which DDRs play crucial roles. We discuss recent data from studies that demonstrate the involvement of DDRs in tumor proliferation, cancer mutations, drug resistance, inflammation, neo-angiogenesis and metastasis. DDRs could be potential targets in cancer and we conclude this review by discussing the different ways to inhibits them.
10.1080/19336918.2018.1465156
Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia.
K Bhanumathy Kalpana,Balagopal Amrutha,Vizeacoumar Frederick S,Vizeacoumar Franco J,Freywald Andrew,Giambra Vincenzo
Cancers
Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell-cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal-epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.
10.3390/cancers13020184
Discoidin Domain Receptor 2: A New Target in Cancer.
Xu Xiaoxiao,Yu Tong,Wang Zhenxing
Oncology research and treatment
BACKGROUND:Discoidin domain receptor is a new and unique type of receptor tyrosine kinases, which binds to collagen, the main compose of an extracellular matrix. DDR1 was identified to mediate cell aggregation, and dysregulation of DDR2 has also been shown to be involved in tumor pathogenesis, although its role in cancer development and progression remains controversial. SUMMARY:Abnormal expression and mutations of DDR2 have been reported in several cancer types and its participation in different aspects of tumor progression, including proliferation, migration, invasion, metastasis, epithelial-mesenchymal transition, and chemotherapy resistance. Moreover, novel DDR2 inhibitors have been designed and indicate a therapeutic effect for the cancer treatment. KEY MESSAGES:In this review, we summarize the current knowledge on the role of DDR2 in cancer promotion and the potential therapeutic value of targeting DDR2.
10.1159/000519645
Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies.
Gao Yuan,Zhou Jiuli,Li Jin
Cancer science
Discoidin domain receptors (DDR), including DDR1 and DDR2, are special types of the transmembrane receptor tyrosine kinase superfamily. DDR are activated by binding to the triple-helical collagen and, in turn, DDR can activate signal transduction pathways that regulate cell-collagen interactions involved in multiple physiological and pathological processes such as cell proliferation, migration, apoptosis, and cytokine secretion. Recently, DDR have been found to contribute to various diseases, including cancer. In addition, aberrant expressions of DDR have been reported in various human cancers, which indicates that DDR1 and DDR2 could be new targets for cancer treatment. Considerable effort has been made to design DDR inhibitors and several molecules have shown therapeutic effects in pre-clinical models. In this article, we review the recent literature on the role of DDR in cancer progression, the development status of DDR inhibitors, and the clinical potential of targeting DDR in cancer therapies.
10.1111/cas.14789
Discoidin Domain Receptor 1, a Potential Biomarker and Therapeutic Target in Hepatocellular Carcinoma.
Wu Linghong,Zhao Xinhua,Ma Huan,Zhang Lili,Li Xiaoan
International journal of general medicine
Hepatocellular carcinoma (HCC) is still one of the most lethal human cancers in the world due to its high degree of malignancy, easy invasion and metastasis, poor therapeutic effect and poor prognosis. Nowadays, there is no very effective diagnosis and treatment method. It is crucial to elucidate the underlying pathogenesis and mechanisms of HCC for developing new and effective diagnostic/prognostic biomarkers and therapies. Discoidin domain receptors (DDRs) belong to the family of transmembrane receptor tyrosine kinases (RTKs) and are recognized as playing central regulatory roles in a variety of high incidence human diseases, including tumors. DDRs have two members, DDR1 and DDR2. The role of DDR1 in several tumors has been extensively studied, and many researchers have identified it as a powerful candidate target for the development of functional and effective tumor treatment inhibitors. However, its role and mechanism in HCC are ill defined. In this article, we review the advanced insights into the progression of DDR1 in HCC, particularly the ligands and mechanisms in invasion and metastasis, which may open new avenues for the therapeutic utility of HCC.
10.2147/IJGM.S348110
Insulin/IGF signaling and discoidin domain receptors: An emerging functional connection.
Vella Veronica,Malaguarnera Roberta,Nicolosi Maria Luisa,Morrione Andrea,Belfiore Antonino
Biochimica et biophysica acta. Molecular cell research
The insulin/insulin-like growth factor system (IIGFs) plays a fundamental role in the regulation of prenatal and postnatal growth, metabolism and homeostasis. As a consequence, dysregulation of this axis is associated with growth disturbance, type 2 diabetes, chronic inflammation and tumor progression. A functional crosstalk between IIGFs and discoidin domain receptors (DDRs) has been recently discovered. DDRs are non-integrin collagen receptors that canonically undergo slow and long-lasting autophosphorylation after binding to fibrillar collagen. While both DDR1 and DDR2 functionally interact with IIGFs, the crosstalk with DDR1 is so far better characterized. Notably, the IIGFs-DDR1 crosstalk presents a feed-forward mechanism, which does not require collagen binding, thus identifying novel non-canonical action of DDR1. Further studies are needed to fully explore the role of this IIGFs-DDRs functional loop as potential target in the treatment of inflammatory and neoplastic disorders.
10.1016/j.bbamcr.2019.118522
Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery.
Drug discovery today
Discoidin domain receptor (DDR) 1 and 2 are transmembrane receptors that belong to the family of receptor tyrosine kinases (RTK). Upon collagen binding, DDRs transduce cellular signaling involved in various cell functions, including cell adhesion, proliferation, differentiation, migration, and matrix homeostasis. Altered DDR function resulting from either mutations or overexpression has been implicated in several types of disease, including atherosclerosis, inflammation, cancer, and tissue fibrosis. Several established inhibitors, such as imatinib, dasatinib, and nilotinib, originally developed as Abelson murine leukemia (Abl) kinase inhibitors, have been found to inhibit DDR kinase activity. As we review here, recent discoveries of novel inhibitors and their co-crystal structure with the DDR1 kinase domain have made structure-based drug discovery for DDR1 amenable.
10.1016/j.drudis.2014.09.025
Complex roles of discoidin domain receptor tyrosine kinases in cancer.
Mehta V,Chander H,Munshi A
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico
Discoidin domain receptors, DDR1 and DDR2 are members of the receptor tyrosine kinase (RTK) family that serves as a non-integrin collagen receptor and were initially identified as critical regulators of embryonic development and cellular homeostasis. In recent years, numerous studies have focused on the role of these receptors in disease development, in particular, cancer where they have been reported to augment ECM remodeling, invasion, drug resistance to facilitate tumor progression and metastasis. Interestingly, accumulating evidence also suggests that DDRs promote apoptosis and suppress tumor progression in various human cancers due to which their functions in cancer remain ill-defined and presents a case of an interesting therapeutic target. The present review has discussed the role of DDRs in tumorigenesis and the metastasis.
10.1007/s12094-021-02552-6
Discoidin Domain Receptors: Potential Actors and Targets in Cancer.
Rammal Hassan,Saby Charles,Magnien Kevin,Van-Gulick Laurence,Garnotel Roselyne,Buache Emilie,El Btaouri Hassan,Jeannesson Pierre,Morjani Hamid
Frontiers in pharmacology
The extracellular matrix critically controls cancer cell behavior by inducing several signaling pathways through cell membrane receptors. Besides conferring structural properties to tissues around the tumor, the extracellular matrix is able to regulate cell proliferation, survival, migration, and invasion. Among these receptors, the integrins family constitutes a major class of receptors that mediate cell interactions with extracellular matrix components. Twenty years ago, a new class of extracellular matrix receptors has been discovered. These tyrosine kinase receptors are the two discoidin domain receptors DDR1 and DDR2. DDR1 was first identified in the Dictyostelium discoideum and was shown to mediate cell aggregation. DDR2 shares highly conserved sequences with DDR1. Both receptors are activated upon binding to collagen, one of the most abundant proteins in extracellular matrix. While DDR2 can only be activated by fibrillar collagen, particularly types I and III, DDR1 is mostly activated by type I and IV collagens. In contrast with classical growth factor tyrosine kinase receptors which display a rapid and transient activation, DDR1 and DDR2 are unique in that they exhibit delayed and sustained receptor phosphorylation upon binding to collagen. Recent studies have reported differential expression and mutations of DDR1 and DDR2 in several cancer types and indicate clearly that these receptors have to be taken into account as new players in the different aspects of tumor progression, from non-malignant to highly malignant and invasive stages. This review will discuss the current knowledge on the role of DDR1 and DDR2 in malignant transformation, cell proliferation, epithelial to mesenchymal transition, migratory, and invasive processes, and finally the modulation of the response to chemotherapy. These new insights suggest that DDR1 and DDR2 are new potential targets in cancer therapy.
10.3389/fphar.2016.00055
Discoidin domain receptor inhibitors as anticancer agents: A systematic review on recent development of DDRs inhibitors, their resistance and structure activity relationship.
Bioorganic chemistry
Discoidin domain receptors (DDRs) are one of the less explored targets for the treatment of cancer which belong to receptor tyrosine kinases family. Discoidin domain receptors (DDRs) are a collagen-activated receptor tyrosine kinase and essential for controlling cellular functions like proliferation, morphogenesis, adhesion, differentiation, invasion, matrix remodeling, and migration. Although there are many targets and their inhibitors are reported which treat cancer. But most of drugs were amalgamated with moderate to severe side effects. This results in untreated cancerous cells. One of the reasons that cancer is considered challenging to treat because the targets were mutating rapidly and the inhibitor become less potent. The target identification is a tedious task for the researchers from the early 1990 s till date. When it comes to cancer, there has not been any magical stick to treat it undisputedly. Therefore, need for discovery of new receptor may helpful to overcome these difficulties. The development of DDR inhibitors has received a lot of attention ever since the target was discovered. In this review we have reported the development of most promising DDR1 and DDR2 small molecule inhibitors from the perspective of medicinal chemistry. We have also discussed about the clinical trials, recent patents, selectivity biological activity, and structure-activity relationship (SAR) of DDR1 and DDR2 inhibitors.
10.1016/j.bioorg.2022.106215
Focusing on discoidin domain receptors in premalignant and malignant liver diseases.
Frontiers in oncology
Discoidin domain receptors (DDRs) are receptor tyrosine kinases on the membrane surface that bind to extracellular collagens, but they are rarely expressed in normal liver tissues. Recent studies have demonstrated that DDRs participate in and influence the processes underlying premalignant and malignant liver diseases. A brief overview of the potential roles of DDR1 and DDR2 in premalignant and malignant liver diseases is presented. DDR1 has proinflammatory and profibrotic benefits and promotes the invasion, migration and liver metastasis of tumour cells. However, DDR2 may play a pathogenic role in early-stage liver injury (prefibrotic stage) and a different role in chronic liver fibrosis and in metastatic liver cancer. These views are critically significant and first described in detail in this review. The main purpose of this review was to describe how DDRs act in premalignant and malignant liver diseases and their potential mechanisms through an in-depth summary of preclinical and studies. Our work aims to provide new ideas for cancer treatment and accelerate translation from bench to bedside.
10.3389/fonc.2023.1123638
Signaling by discoidin domain receptor 1 in cancer metastasis.
Cell adhesion & migration
Collagen is the most abundant component of tumor extracellular matrix (ECM). ECM collagens are known to directly interact with the tumor cells via cell surface receptor and play crucial role in tumor cell survival and promote tumor progression. Collagen receptor DDR1 is a member of receptor tyrosine kinase (RTK) family with a unique motif in the extracellular domain resembling Dictyostelium discoideum protein discoidin-I. DDR1 displays delayed and sustained activation upon interaction with collagen and recent findings have demonstrated that DDR1-collagen signaling play important role in cancer progression. In this review, we discuss the current knowledge on the role of DDR1 in cancer metastasis and possibility of a potential therapeutic approach of DDR1 targeted therapy in cancer.
10.1080/19336918.2018.1520556
Meeting report - first discoidin domain receptors meeting.
Auguste Patrick,Leitinger Birgit,Liard Christelle,Rocher Virginie,Azema Laurent,Saltel Frederic,Santamaria David
Journal of cell science
For the first time, a meeting dedicated to the tyrosine kinase receptors DDR1 and DDR2 took place in Bordeaux, a famous and historical city in the south of France. Over the course of 3 days, the meeting allowed 60 participants from 11 different countries to exchange ideas and their new findings about these unique collagen receptors, focusing on their role in various physiological and pathological conditions and addressing their mechanisms of regulation and signalling. The involvement of these receptors in different pathologies was also considered, with emphasis on cancer development and potential therapeutic applications. Here, we summarize the key elements of this meeting.
10.1242/jcs.243824
Discoidin domain receptor 1 may be involved in biological barrier homeostasis.
Journal of clinical pharmacy and therapeutics
WHAT IS KNOWN AND OBJECTIVE:Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase involved in the pathological processes of several diseases, such as keloid formation, renal fibrosis, atherosclerosis, tumours, and inflammatory processes. The biological barrier is the first line of defence against pathogens, and its disruption is closely related to diseases. In this review, we attempt to elucidate the relationship between DDR1 and the biological barrier, explore the potential biological value of DDR1, and review the current research status and clinical potential of DDR1-selective inhibitors. METHODS:We conducted an extensive literature search on PubMed to collect studies on the relevance of DDR1 to biological barriers and DDR1-selective inhibitors. With these studies, we explored the relationship between DDR1 and biological barriers and briefly reviewed representative DDR1-selective inhibitors that have been reported in recent years. RESULTS AND DISCUSSION:First, the review of the potential mechanisms by which DDR1 regulates biological barriers, including the epithelial, vascular, glomerular filtration, blood-labyrinth, and blood-brain barriers. In the body, DDR1 dysfunction and aberrant expression may be involved in the homeostasis of the biological barrier. Secondly, the review of DDR1 inhibitors reported in recent years shows that DDR1-targeted inhibition is an attractive and promising pharmacological intervention. WHAT IS NEW AND CONCLUSIONS:This review shows that DDR1 is involved in various physiological and pathological processes and in the regulation of biological barrier homeostasis. However, studies on DDR1 and biological barriers are still scarce, and further studies are needed to elucidate their specific mechanisms. The development of targeted inhibitors provides a new direction and idea to study the mechanism of DDR1.
10.1111/jcpt.13705
Discoidin domain receptors in disease.
Borza Corina M,Pozzi Ambra
Matrix biology : journal of the International Society for Matrix Biology
Discoidin domain receptors, DDR1 and DDR2, lie at the intersection of two large receptor families, namely the extracellular matrix and tyrosine kinase receptors. As such, DDRs are uniquely positioned to function as sensors for extracellular matrix and to regulate a wide range of cell functions from migration and proliferation to cytokine secretion and extracellular matrix homeostasis/remodeling. While activation of DDRs by extracellular matrix collagens is required for normal development and tissue homeostasis, aberrant activation of these receptors following injury or in disease is detrimental. The availability of mice lacking DDRs has enabled us to identify key roles played by these receptors in disease initiation and progression. DDR1 promotes inflammation in atherosclerosis, lung fibrosis and kidney injury, while DDR2 contributes to osteoarthritis. Furthermore, both DDRs have been implicated in cancer progression. Yet the mechanisms whereby DDRs contribute to disease progression are poorly understood. In this review we highlight the mechanisms whereby DDRs regulate two important processes, namely inflammation and tissue fibrosis. In addition, we discuss the challenges of targeting DDRs in disease. Selective targeting of these receptors requires understanding of how they interact with and are activated by extracellular matrix, and whether their cellular function is dependent on or independent of receptor kinase activity.
10.1016/j.matbio.2013.12.002
Novel roles for cooperating collagen receptor families in fibrotic niches.
Current opinion in cell biology
Recent data indicate that integrin and non-integrin collagen receptors cooperate in the fibrosis-specific microenvironment (i.e., the fibrotic niche). In certain tumor types, DDR1 can regulate the interaction with collagen III to regulate dormancy and metastasis, whereas in other tumor types, DDR1 can be shed and used to reorganize collagen. DDR1 expressed on tumor cells, together with DDR2 and α11β1 integrin expressed on cancer-associated fibroblasts, can increase tumor tissue stiffness. Integrin α1β1 and α2β1 are present on immune cells where they together with the immunosuppressive collagen receptor LAIR-1 can mediate binding to intratumor collagens. In summary, collagen-binding integrins together with DDRs, can create fibrillar collagen niches that act as traps to hinder immune cell trafficking into the tumor cell mass. Binding of collagens via LAIR-1 on immune cells in turn results in CD8+T-cell exhaustion. Continued studies of these complex interactions are needed for successful new stroma-based therapeutic interventions. In the current review, we will summarize recent data on collagen receptors with a special focus on their potential role in tumor fibrosis and highlight their collaborative roles in tumor fibrotic niches.
10.1016/j.ceb.2023.102273
Research progress of DDR1 inhibitors in the treatment of multiple human diseases.
European journal of medicinal chemistry
Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase (RTK) and plays pivotal roles in regulating cellular functions such as proliferation, differentiation, invasion, migration, and matrix remodeling. DDR1 is involved in the occurrence and progression of many human diseases, including cancer, fibrosis, and inflammation. Therefore, DDR1 represents a highly promising therapeutic target. Although no selective small-molecule inhibitors have reached clinical trials to date, many molecules have shown therapeutic effects in preclinical studies. For example, BK40143 has demonstrated significant promise in the therapy of neurodegenerative diseases. In this context, our perspective aims to provide an in-depth exploration of DDR1, encompassing its structure characteristics, biological functions, and disease relevance. Furthermore, we emphasize the importance of understanding the structure-activity relationship of DDR1 inhibitors and highlight the unique advantages of dual-target or multitarget inhibitors. We anticipate offering valuable insights into the development of more efficacious DDR1-targeted drugs.
10.1016/j.ejmech.2024.116291
New functions of DDR1 collagen receptor in tumor dormancy, immune exclusion and therapeutic resistance.
Frontiers in oncology
The tumor microenvironment facilitates cancer progression and therapeutic resistance. Tumor collagens and their architecture play an essential role in this process. However, little is known about the mechanisms by which tumor cells sense and respond to this extracellular matrix environment. Recently, the Discoidin Domain Receptor 1 (DDR1), a collagen receptor and tyrosine kinase has emerged as an important player in this malignant process, although the underlying signaling mechanisms remain unclear. Here, we review new DDR1 functions in tumor dormancy following dissemination, immune exclusion and therapeutic resistance induced by stromal collagens deposition. We also discuss the signaling mechanisms behind these tumor activities and the therapeutic strategies aiming at targeting these collagens-dependent tumor responses.
10.3389/fonc.2022.956926
New target DDR1: A "double-edged sword" in solid tumors.
Biochimica et biophysica acta. Reviews on cancer
Globally, cancer is a major catastrophic disease that seriously threatens human health. Thus, there is an urgent need to find new strategies to treat cancer. Among them, identifying new targets is one of the best ways to treat cancer at present. Especially in recent years, scientists have discovered many new targets and made breakthroughs in the treatment of cancer, bringing new hope to cancer patients. As one of the novel targets for cancer treatment, DDR1 has attracted much attention due to its unique role in cancer. Hence, here, we focus on a new target, DDR1, which may be a "double-edged sword" of human solid tumors. In this review, we provide a comprehensive overview of how DDR1 acts as a "double-edged sword" in cancer. First, we briefly introduce the structure and normal physiological function of DDR1; Second, we delineate the DDR1 expression pattern in single cells; Next, we sorte out the relationship between DDR1 and cancer, including the abnormal expression of DDR1 in cancer, the mechanism of DDR1 and cancer occurrence, and the value of DDR1 on cancer prognosis. In addition, we introduced the current status of global drug and antibody research and development targeting DDR1 and its future design prospects; Finally, we summarize and look forward to designing more DDR1-targeting drugs in the future to make further progress in the treatment of solid tumors.
10.1016/j.bbcan.2022.188829
Dichotomy of the function of DDR1 in cells and disease progression.
Yeh Yi-Chun,Lin Hsi-Hui,Tang Ming-Jer
Biochimica et biophysica acta. Molecular cell research
Discoidin domain receptors DDR1 and DDR2 are collagen receptor tyrosine kinases that have many roles in tissue development and disease progression. Under physiological conditions, DDR1 is predominantly expressed in epithelial cells and functions to maintain cell differentiation and tissue homeostasis. A switch in expression from DDR1 to DDR2 occurs during epithelial-to-mesenchymal transition. However, opposite effects of DDR1 are reported to be involved in the progression of cancer and fibrotic diseases. Accumulating evidence suggests that DDR1 is involved in pro-metastasis and pro-survival signals. This review summarizes the roles of DDR1 in epithelial cell differentiation, cell migration, cancer progression and tissues fibrosis and highlights how the dichotomous functions of DDR1 may relevant to different cell types and statues. Elucidation of the underlying mechanism of the dichotomous functions of DDR1 will help to develop DDR1 as a therapeutic target.
10.1016/j.bbamcr.2019.04.003
The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer.
Elkamhawy Ahmed,Lu Qili,Nada Hossam,Woo Jiyu,Quan Guofeng,Lee Kyeong
International journal of molecular sciences
Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.
10.3390/ijms22126535
A novel functional crosstalk between DDR1 and the IGF axis and its relevance for breast cancer.
Belfiore Antonino,Malaguarnera Roberta,Nicolosi Maria Luisa,Lappano Rosamaria,Ragusa Marco,Morrione Andrea,Vella Veronica
Cell adhesion & migration
In the last decades increasing importance has been attributed to the Insulin/Insulin-like Growth Factor signaling (IIGFs) in cancer development, progression and resistance to therapy. In fact, IIGFs is often deregulated in cancer. In particular, the mitogenic insulin receptor isoform A (IR-A) and the insulin-like growth factor receptor (IGF-1R) are frequently overexpressed in cancer together with their cognate ligands IGF-1 and IGF-2. Recently, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis. Herein, we review recent findings indicating that DDR1 is as a novel modulator of IR and IGF-1R expression and function. DDR1 functionally interacts with IR and IGF-1R and enhances the biological actions of insulin, IGF-1 and IGF-2. Conversely, DDR1 is upregulated by IGF-1, IGF-2 and insulin through the PI3K/AKT/miR-199a-5p circuit. Furthermore, we discuss the role of the non-canonical estrogen receptor GPER1 in the DDR1-IIGFs crosstalk. These data suggest a wider role of DDR1 as a regulator of cell response to hormones, growth factors, and signals coming from the extracellular matrix.
10.1080/19336918.2018.1445953
DDR1-targeted therapies: current limitations and future potential.
Drug discovery today
Discoidin domain receptor (DDR)-1 has a crucial role in regulating vital processes, including cell differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. Overexpression or activation of DDR1 in various pathological scenarios makes it a potential therapeutic target for the treatment of cancer, fibrosis, atherosclerosis, and neuropsychiatric, psychiatric, and neurodegenerative disorders. In this review, we summarize current therapeutic approaches targeting DDR1 from a medicinal chemistry perspective. Furthermore, we analyze factors other than issues of low selectivity and risk of resistance, contributing to the infrequent success of DDR1 inhibitors. The complex interplay between DDR1 and the extracellular matrix (ECM) necessitates additional validation, given that DDR1 might exhibit complex and synergistic interactions with other signaling molecules during ECM regulation. The mechanisms involved in DDR1 regulation in cancer and inflammation-related diseases also remain unknown.
10.1016/j.drudis.2024.103975
Multifaceted collagen-DDR1 signaling in cancer.
Trends in cell biology
In addition to immune cells and fibroblasts, the tumor microenvironment (TME) comprises an extracellular matrix (ECM) which contains collagens (COLs) whose architecture and remodeling dictate cancer development and progression. COL receptors expressed by cancer cells sense signals generated by microenvironmental alterations in COL state to regulate cell behavior and metabolism. Discoidin domain receptor 1 (DDR1) is a key sensor of COL fiber state and composition that controls tumor cell metabolism and growth, response to therapy, and patient survival. This review focuses on DDR1 to NRF2 signaling, its modulation of autophagy and macropinocytosis (MP), and its role in cancer and other diseases. Elucidating the regulation of DDR1 activity and expression under different pathophysiological conditions will facilitate the discovery of new therapeutics.
10.1016/j.tcb.2023.08.003