What Is PTPN18 and Its Role in Cancer?

Protein Tyrosine Phosphatase Non-Receptor Type 18 (PTPN18) is a member of a large family of enzymes called protein tyrosine phosphatases (PTPs). These enzymes act as molecular switches inside cells by removing chemical tags known as phosphate groups from proteins, a process called dephosphorylation. This removal alters a target protein’s activity, regulating cellular processes like growth, differentiation, and division.

PTPN18 is also known by other names, including BDP1 (Breast-cancer-downregulated phosphatase 1). It is categorized as a non-receptor type enzyme, which means it operates freely within the cell’s interior rather than being fixed to the cell membrane.

The Biological Role of PTPN18

In a healthy state, PTPN18 helps manage several fundamental cellular behaviors. Its primary responsibilities include the regulation of cell adhesion, which is how cells attach to one another, and cell migration. It also helps maintain the organization of the cytoskeleton, the network of protein filaments that provides the cell with shape and internal structure.

PTPN18 accomplishes these tasks by targeting specific proteins, referred to as substrates. One of its well-documented substrates is a protein known as p130Cas. By dephosphorylating p130Cas, PTPN18 helps to fine-tune the signaling pathways that control how a cell moves and organizes its internal scaffolding.

The enzyme’s structure includes a catalytic domain at one end that removes the phosphate groups and a non-catalytic region with a PEST motif. This motif acts as a docking site, facilitating interactions with other proteins and ensuring PTPN18 acts on the correct targets. This structural organization allows it to participate in signaling complexes to modulate cellular pathways.

PTPN18’s Connection to Cancer

The function of PTPN18 is often altered in cancer. In many types of tumors, the amount of PTPN18 protein is much higher than in normal, healthy tissues, which disrupts the balance of cellular signaling and contributes to disease progression. This is particularly evident in certain forms of breast cancer.

Its role is prominent in HER2-positive breast cancer, an aggressive subtype of the disease. In these cancer cells, PTPN18 interacts with and dephosphorylates the HER2 receptor itself. This action can paradoxically enhance the signaling pathways that drive cancer cell proliferation and survival, contributing to tumor growth.

Heightened levels of PTPN18 are also strongly linked to cancer metastasis, the process by which cancer cells spread from the primary tumor. This is connected to its normal role in regulating cell migration, which becomes amplified in a cancer setting. This allows cancer cells to detach from the main tumor, invade adjacent tissues, and form new tumors elsewhere.

The influence of PTPN18 is not uniform across all cancers and can appear contradictory. While it often promotes progression, some studies have identified it as a tumor suppressor in specific contexts, such as in hepatocellular carcinoma. This dual role suggests its effect depends on the cellular environment and the specific signaling networks active in a particular cancer type.

PTPN18 as a Prognostic Marker

The amount of PTPN18 in tumor cells has clinical implications, making it a useful prognostic marker. A prognostic marker is a measurable biological feature that helps predict the likely course and outcome of a disease. By measuring PTPN18 levels, clinicians can gain insight into how aggressive a cancer might be.

In breast cancer, studies show a direct correlation between high levels of PTPN18 expression and a poorer prognosis. A “poorer prognosis” often means a greater likelihood of disease recurrence after treatment or a higher chance that the cancer will metastasize.

This information is valuable for tailoring patient care. If a patient’s tumor has elevated PTPN18, it may signal to the oncology team that a more aggressive treatment strategy or more vigilant follow-up monitoring is warranted. The expression level is determined by analyzing a sample of the tumor tissue obtained during a biopsy.

Therapeutic Targeting of PTPN18

Given its role in promoting cancer progression, PTPN18 has emerged as an attractive molecule for new cancer treatments. The strategy uses targeted therapy, which involves drugs designed to interfere with specific molecules that cancer cells rely on to grow and spread. Unlike traditional chemotherapy, targeted therapies are more precise.

The rationale for targeting PTPN18 is that a drug blocking its activity could slow or halt metastasis. Developing an inhibitor for PTPN18 could offer a new way to treat aggressive cancers where the enzyme is overexpressed, such as HER2-positive breast cancer. Such a drug would work by preventing PTPN18 from dephosphorylating its target proteins.

However, creating effective drugs that target phosphatases is a significant scientific challenge. These enzymes have a highly conserved active site, making it difficult to design small molecules that block one particular phosphatase without affecting others. Despite these hurdles, research into developing PTPN18 inhibitors is an active area of investigation, holding promise for future therapies to combat metastatic cancer.