DDR2

Official Full Name

discoidin domain receptor tyrosine kinase 2

Organism

Homo sapiens

GeneID

4921

Background

This gene encodes a member of the discoidin domain receptor subclass of the receptor tyrosine kinase (RTKs) protein family. RTKs play a key role in the communication of cells with their microenvironment. The encoded protein is a collagen-induced receptor that activates signal transduction pathways involved in cell adhesion, proliferation, and extracellular matrix remodeling. This protein is expressed in numerous cell types and may alos be involved in wound repair and regulate tumor growth and invasiveness. Mutations in this gene are the cause of short limb-hand type spondylometaepiphyseal dysplasia. [provided by RefSeq, Aug 2017]

Synonyms

TKT; WRCN; MIG20a; NTRKR3; TYRO10;

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Detailed Information

Discoidin structural domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs) whose dysregulation is associated with a variety of diseases, including cancer, chronic inflammation, and fibrosis. DDR family members (DDR1a-e and DDR2) are widely expressed, with DDR1 expressed predominantly in epithelial cells and DDR2 expressed predominantly in hypodermal cells. DDR2 is a member of the discoidin domain receptor family, which is characterized by the presence of a discoidin domain in their extracellular region.

Structure and Function of DDR2

Overexpression of DDR1 promotes tumor cell proliferation (including regulation of tumor-infiltrating CD4+ and CD8+ T cells), while silencing or knockdown of DDR1 reduces tumor cell growth. Overexpression of DDR1/2 in cells expressing integrins α1β1 and α2β1 increased the level of integrin activation-mediated cell adhesion. Integrin β1 promotes cell differentiation by down-regulating E-cadherin expression, whereas DDR1 promotes cell differentiation by increasing the stability of E-cadherin membrane proteins. Furthermore, deletion of either E-cadherin or DDR1 is enough to promote increased cortical contractility, which leads to loss of cell-cell adhesion. It has been shown that DDR1 and integrin α2β1 upregulate N-cadherin by interacting with transforming growth factor β-inducible protein I (TGFβI), thereby promoting growth, invasion, and metastasis. Of interest, DDR1 expression can be mediated through the secretory pathway Ca2+ -ATPase (SPCA2) via collagen I and miR-199B-5p.

Pathological Implications of DDR2

DDR2 has been implicated in various pathological conditions, including tissue repair, fibrosis, and cancer. In tissue repair, DDR2 plays a crucial role in regulating fibroblast proliferation and migration, which are essential for wound healing. DDR2 knockout mice have shown delayed wound healing and impaired fibroblast function, highlighting the importance of DDR2 in tissue repair.

Extracellular matrix (ECM) interactions regulate the cellular transcriptome and proteome, thereby determining cell fate. Traumatic heterotopic ossification (HO) is a disorder characterized by abnormal differentiation of mesenchymal lineage (MLin) cells, which form bone within the soft tissues of the musculoskeletal system after trauma. Recent studies have shown that HO is affected by ECM-MLin cell receptor signaling, but how ECM binding affects cellular outcomes remains unclear. The cell surface receptor for fibrillar collagen, discoidin structural domain receptor 2 (DDR2), is a key MLin cell regulator during HO formation. DDR2 signaling is inhibited by constitutive or conditional Ddr2 deletion or pharmacological inhibition. Mechanistically, DDR2 perturbation alters focal adhesion orientation and subsequent stromal organization, regulating MLin cell signaling mediated by focal adhesion kinase (FAK) and Yes1 As- social transcriptional regulator and WW domain-containing transcriptional regulator 1 (YAP/TAZ). Thus, ECM-DDR2 interaction is a key driver of HO and may serve as an unknown therapeutic target for the treatment of HO.

References:

Chen L, Kong X, Fang Y, et al. Recent Advances in the Role of Discoidin Domain Receptor Tyrosine Kinase 1 and Discoidin Domain Receptor Tyrosine Kinase 2 in Breast and Ovarian Cancer. Front Cell Dev Biol. 2021;9:747314. Published 2021 Nov 3. doi:10.3389/fcell.2021.747314
Pagani CA, Bancroft AC, Tower RJ, et al. Discoidin domain receptor 2 regulates aberrant mesenchymal lineage cell fate and matrix organization. Sci Adv. 2022;8(51):eabq6152. doi:10.1126/sciadv.abq6152

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