CDCP1 - CUB domain containing protein 1 |Elisa - Clia - Antibody - Protein

Background

CDCP1 (CUB Domain Containing Protein 1), also known as CD318 or Trask, is a transmembrane protein widely expressed across cell types, including epithelial cells, stem cells, and notably in certain types of cancer cells. CDCP1 is known for its involvement in various cellular processes, including cell adhesion, migration, and signal transduction. It is a single-pass membrane protein characterized by extracellular CUB domains, which are implicated in protein-protein interactions, especially in cell communication and adhesion mechanisms.

CDCP1 plays a crucial role in cancer biology, as its overexpression or aberrant activation has been observed in multiple malignancies, such as lung, colon, and breast cancer, where it contributes to processes like invasion, metastasis, and resistance to apoptosis. This makes CDCP1 an important molecule in cancer progression and a potential target for therapeutic interventions. Moreover, CDCP1 is implicated in non-cancerous biological pathways, including wound healing and tissue remodeling, which involve dynamic changes in cell adhesion and migration.

Protein Structure

CDCP1 is a type I transmembrane protein with a complex structure that is essential for its functions:

Extracellular Domain:

• The extracellular region of CDCP1 contains CUB domains (C1r/C1s, Uegf, and Bmp1), which are modules that facilitate protein-protein interactions, especially in the context of cell adhesion and signaling. These domains provide specificity for ligand binding and play a role in mediating interactions with other cell surface proteins or extracellular matrix (ECM) components.
• The CUB domains also facilitate the cleavage of CDCP1 by specific proteases, which can modulate its activity. This cleavage event is often carried out by serine proteases like matriptase and is important for triggering downstream signaling cascades.

Transmembrane Domain:

• CDCP1 is a single-pass transmembrane protein, meaning it crosses the cell membrane only once. This domain anchors CDCP1 to the cell membrane, which is essential for its role in cell signaling.
• The transmembrane domain helps CDCP1 position itself in close proximity to other membrane-bound proteins and signaling complexes, enabling its participation in signal transduction pathways.

Intracellular (Cytoplasmic) Domain:

• The intracellular portion of CDCP1 contains several tyrosine residues that are phosphorylated in response to cellular signals. Key phosphorylation sites, such as tyrosine 734 and 743, are involved in the recruitment of intracellular signaling molecules, particularly Src family kinases and PKCδ (Protein Kinase C delta).
• This phosphorylation event is crucial for CDCP1’s role in transmitting signals that regulate cell motility, survival, and other behaviors associated with cancer progression. When phosphorylated, these residues create docking sites for signaling proteins, amplifying downstream pathways associated with migration and adhesion.

Classification and Subtypes

CDCP1 belongs to a family of CUB domain-containing proteins. These proteins are involved in diverse cellular functions, including development, tissue remodeling, and immune responses, largely due to their interactions with ECM components and other cell surface proteins. Although no specific subtypes of CDCP1 have been reported, variations in CDCP1 post-translational modifications, such as phosphorylation and proteolytic cleavage, lead to functional changes that can influence cellular outcomes.

Function and Biological Significance

CDCP1 serves multiple cellular roles, primarily in signal transduction related to cell adhesion, migration, and survival:

Regulation of Cell Adhesion and Migration:

• CDCP1 plays a role in cell adhesion dynamics, which is particularly relevant in the context of cancer cell invasion and metastasis. Phosphorylation of CDCP1 leads to the recruitment of Src kinases, activating signaling pathways that disrupt adhesion to the ECM and facilitate cell detachment. This function enables cancer cells to migrate and invade new tissues.
• CDCP1-mediated signaling has been shown to enhance migration by promoting cytoskeletal rearrangements, which are necessary for cell movement. This property is not limited to cancer but is also relevant in normal physiological processes like wound healing, where cells must migrate to repair tissue.

Survival Signaling:

• CDCP1 is involved in anti-apoptotic signaling pathways, allowing cells to evade programmed cell death. This is particularly relevant in cancer, where CDCP1 expression is linked to enhanced survival of tumor cells under stress conditions, such as hypoxia or detachment from the ECM (anoikis resistance). The ability of CDCP1 to promote survival under these conditions is a critical factor in tumor metastasis.
• The recruitment of PKCδ upon CDCP1 phosphorylation triggers signaling pathways that inhibit apoptosis, thus enabling cancer cells to survive as they travel through the bloodstream or lymphatic system to colonize new sites.

Interactions with the Extracellular Matrix:

• CDCP1 modulates interactions with ECM proteins, which can alter cellular behavior in various contexts. By influencing ECM binding, CDCP1 plays a role in cell motility and adhesion, impacting processes such as tumor invasion and tissue remodeling.
• Through its CUB domains, CDCP1 interacts with matrix metalloproteases (MMPs) and other proteolytic enzymes that degrade ECM, further facilitating cancer cell invasion and migration.

Role in Cancer Progression:

• CDCP1’s functions in cell detachment, migration, and survival make it an important factor in cancer metastasis. Its overexpression has been correlated with poor prognosis in various cancers, including lung, colon, and breast cancers. It is often upregulated in cancer cells, where it promotes invasive and metastatic behavior by enhancing motility and survival signaling.

Clinical Issues

The clinical relevance of CDCP1 has been explored extensively in cancer biology, as its upregulation and activation correlate with aggressive tumor behavior. Specific clinical considerations include:

Prognostic Marker in Cancer:

• Elevated CDCP1 expression is associated with poor prognosis in many cancers. High CDCP1 levels often indicate a more invasive and metastatic tumor phenotype, and its expression correlates with shorter patient survival in cancers such as lung, breast, and colorectal cancers.
• CDCP1’s phosphorylation status could also serve as a biomarker, as phosphorylation is indicative of its active signaling state, which contributes to cancer progression.

Therapeutic Target:

• Given CDCP1’s role in cancer invasion and metastasis, it has emerged as a potential target for therapeutic intervention. Inhibitors of CDCP1 function, particularly those that block its interaction with Src kinases or its proteolytic cleavage, have been explored as anti-cancer strategies. Blocking CDCP1 could limit tumor cell migration and survival, reducing the risk of metastasis.
• Antibody-based therapies targeting CDCP1 are under investigation to interfere with its extracellular domain, potentially disrupting its interactions and signaling functions, thus limiting tumor growth and spread.

Resistance to Anoikis:

• CDCP1’s role in preventing anoikis, a form of cell death induced by detachment from the ECM, is significant in the metastatic spread of cancer. Anoikis resistance enables tumor cells to survive as they disseminate through the bloodstream or lymphatic system, contributing to the establishment of secondary tumors. Therapies targeting CDCP1’s survival signaling pathways may help in sensitizing cancer cells to anoikis, potentially reducing metastatic potential.

Role in Other Diseases:

• While primarily studied in cancer, CDCP1’s role in cellular adhesion and migration implies a potential involvement in wound healing and fibrosis, where tissue remodeling is required. However, more research is needed to elucidate CDCP1’s role in non-cancerous diseases.

Summary

CDCP1, or CUB domain containing protein 1, is a transmembrane protein essential in cell signaling related to adhesion, migration, and survival. Its structure includes CUB domains in the extracellular region, a single-pass transmembrane domain, and intracellular tyrosine phosphorylation sites. These structural elements enable CDCP1 to modulate interactions with the ECM and activate signaling pathways critical for cell detachment, motility, and resistance to apoptosis.

Clinically, CDCP1 has emerged as an important molecule in cancer progression. Overexpressed and hyperphosphorylated in many tumors, CDCP1 contributes to invasion, metastasis, and survival of cancer cells, marking it as a prognostic indicator and potential therapeutic target. Therapeutic approaches targeting CDCP1 aim to reduce metastatic spread by inhibiting its adhesion-related and anti-apoptotic functions. CDCP1’s involvement in processes such as wound healing and tissue remodeling also suggests potential roles beyond oncology, although further research is necessary to understand these functions fully.

In conclusion, CDCP1’s structural characteristics and functional roles underscore its significance in both normal physiology and cancer pathology. Its influence on cell behavior positions it as a critical factor in metastatic disease, and ongoing research may reveal additional therapeutic and diagnostic opportunities related to this protein.