DDR1 promotes metastasis of cervical cancer and downstream phosphorylation signal via binding GRB2

Sep 21, 2026

Cervical cancer remains difficult to treat due to recurrence and metastasis, and the role of discoidin domain receptor 1 (DDR1) in this disease is not well defined. DDR1 expression is elevated in cervical cancer samples, and it is positively associated with the oncogenic transcription factor SOX2, which regulates DDR1 transcription. DDR1 overexpression enhances migration, invasion, and EMT, while DDR1 knockdown produces the opposite effects. In vivo, DDR1 increases pulmonary metastasis. Phosphorylation profiling identifies downstream targets and shows DDR1 directly binds GRB2 to drive malignant signaling and exacerbate metastasis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Disease background and clinical need

Role of DDR1 in cancer biology

SOX2 as a regulatory factor for DDR1

Receptor tyrosine kinase signaling and GRB2 involvement

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN DDR1 promotes metastasis of cervical cancer and downstream phosphorylation signal via binding GRB2 Jin Zhang 1, Aynuer Maimaiti2, Xihan Chang3, Pengcheng Sun3 and Xiaohan Chang 1 ✉ © The Author(s) 2024 | | | | | | --- | --- | --- | --- | | | Cervical cancer is a leading cause of cancer-related death among women and its recurrence and metastasis poses challenges to treatment. Discoidin domain receptor 1 (DDR1) was associated with cellular migration and invasion in several types of cancers. However, its function in cervical cancer is still unclear. In this study, we found that DDR1 was signiﬁcantly more expressed in cervical cancer samples than in normal tissues. SRY-Box transcription factor 2 (SOX2), a known oncogene in cervical cancer, showed a positive correlation with DDR1 and regulated DDR1 transcription, contributing to the elevated expression of DDR1 in cervical cancer. Regarding the function of DDR1 in cervical cancer, the overexpression of DDR1 caused an increase in the migration, invasion, and epithelial-mesenchymal transition (EMT) of cervical cancer cells. In contrast, cervical cancer cells with reduced DDR1 expression exhibited a lower migration rate, fewer invasive cells, and decreased levels of EMT markers. In vivo, mice injected with cervical cancer cells with overexpressed DDR1 showed more pulmonary metastasis and nodule number. Opposite results were found in mice injected with DDR1 silenced cervical cancer cells. Since DDR1 can cause phosphorylation of downstream targets, a phosphorylation omics was employed to reveal the downstream targets of DDR1, including eukaryotic translation initiation factor 4E binding protein 1 and EPH receptor A2 . Furthermore, DDR1 bound directly with Src homology 2 domain of growth factor receptor bound protein 2 (GRB2) which mediated the function of DDR1 in the malignant behaviors of cervical cancer and the phosphorylation of downstream targets. In conclusion, DDR1 binds directly to GRB2 and then affects downstream phosphorylation signals, ultimately exacerbating the metastasis of cervical cancer cells. This work sheds light on the mechanism by which DDR1 functions in cervical cancer cells, providing therapeutic strategy for the treatment of cervical cancer. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Cell Death and Disease (2024)15:849; [https://doi.org/10.1038/s41419-024-07212-5](https://doi.org/10.1038/s41419-024-07212-5) | | | | | | | | INTRODUCTION Cervical cancer is mainly caused by high-risk infection of the human papilloma virus [1], and has become the most commonly malignant tumor of the female reproductive system [2], with approximately 342,000 deaths each year [3] . Recently, due to the increased use of early tests, such as CryoPen and thermal coagulation technologies, the incidence and mortality have declined [4] . However, the overall prognosis of patients, who have advanced or recurrent metastatic cervical cancer, remains poor [5] . Therefore, it is necessary to explore the molecular mechanisms of cervical cancer development. Discoidin domain receptor 1 (DDR1) is a member of receptor tyrosine kinase family and widely expressed in epithelial cells [6]. Current studies indicated that DDR1 participates in key cellular processes, including survival, proliferation, migration and invasion [7]. Besides, increased DDR1 is known to be associated with the progression and poor prognosis of non-small cell lung carcinoma, hepatocellular carcinoma, bladder cancer, and oral squamous cell carcinoma, indicating an important role of DDR1 in in tumor progression [8–11] . Nevertheless, the function and detailed mechanism of DDR1 in the development of cervical cancer remain obscure. SRY-Box transcription factor 2 (SOX2) is a t

FAQs

How does DDR1 expression relate to cervical cancer?

DDR1 is significantly more expressed in cervical cancer samples than in normal tissues, indicating involvement in cervical cancer progression.

What is the functional effect of altering DDR1 levels in cervical cancer cells?

DDR1 overexpression increases migration, invasion, and EMT, while reduced DDR1 expression lowers migration, invasion, and EMT marker levels.

How does DDR1 connect to downstream phosphorylation signaling through GRB2?

DDR1 induces phosphorylation of downstream targets, and it binds directly to GRB2, which mediates DDR1-driven malignant behaviors and phosphorylation signaling.

Sep 21, 2026

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