PTEN, or Phosphatase and Tensin homolog, is a protein found in nearly all human cells. This enzyme is encoded by the PTEN gene. PTEN controls cell division and programmed cell death, helping maintain cellular balance and acting as a biological braking mechanism.
The Role of PTEN as a Tumor Suppressor
The PTEN protein functions as a tumor suppressor, regulating cell division and preventing uncontrolled cell growth. It manages this process by signaling cells to stop dividing and initiating programmed cell death, known as apoptosis.
If cell division occurs too rapidly or without proper control, it can lead to tissue overgrowth and tumor formation. When the PTEN gene is altered or dysfunctional, this braking mechanism is less active, which can contribute to the development of cancer.
Mutations or alterations in the PTEN gene are observed in over 50% of cancer types. For instance, PTEN alterations are found in approximately 80% of prostate cancers and 30-50% of breast cancers. Somatic mutations, acquired during a person’s lifetime, are also found in various cancers, including glioblastomas, astrocytomas, and melanoma.
Inherited mutations in the PTEN gene can increase the risk of developing certain cancers, such as breast cancer, often as part of specific genetic syndromes. PTEN’s influence also extends to controlling cell movement, cell adhesion to surrounding tissues, and the formation of new blood vessels, all of which are relevant to preventing uncontrolled cell proliferation.
How PTEN Works
PTEN performs its functions by acting as an enzyme, specifically a phosphatase. Phosphatases are enzymes that remove phosphate groups from other molecules. The PTEN enzyme primarily dephosphorylates a specific signaling molecule called phosphatidylinositol (3,4,5)-trisphosphate (PIP3).
PIP3 acts as a “second messenger” in cell signaling, promoting cell growth and survival pathways. By removing a phosphate group from PIP3, PTEN converts it into phosphatidylinositol (4,5)-bisphosphate (PIP2). This conversion effectively counteracts the pro-growth signals that PIP3 would otherwise transmit.
This dephosphorylation action is like putting the “brakes” on cellular proliferation and survival pathways. PTEN’s activity directly opposes the actions of other enzymes, such as Class I phosphoinositide 3-kinases (PI3Ks), which produce PIP3. By reducing the levels of PIP3, PTEN helps to inhibit the Akt signaling pathway, a pathway that plays a significant role in regulating cell growth, survival, and migration.
PTEN also possesses a weaker protein phosphatase activity, which is also considered important for its role as a tumor suppressor. This enzyme can modify other proteins by removing phosphate groups. PTEN is found in both the cytosol and nucleus of cells, and it transiently associates with the cell membrane to interact with its primary substrate.
PTEN and Associated Conditions
Dysfunction or mutations in the PTEN gene are linked to a range of health conditions beyond cancer. Several genetic syndromes are directly associated with inherited PTEN mutations, collectively known as PTEN Hamartoma Tumor Syndromes (PHTS). These conditions include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome (BRRS), and Proteus syndrome.
Cowden syndrome is characterized by an increased risk of developing various cancers, including breast, thyroid, and endometrial cancers. Individuals with Cowden syndrome also commonly develop benign growths called hamartomas, which are non-cancerous tumor-like lesions that can appear in different parts of the body, such as the skin, mucous membranes, and gastrointestinal tract.
Bannayan-Riley-Ruvalcaba syndrome (BRRS) shares some features with Cowden syndrome, including benign growths and an increased cancer risk, but it also presents with distinct characteristics. These often include macrocephaly, which is an abnormally large head size, and developmental delays. Proteus syndrome is a rare and complex condition causing overgrowth of various tissues in a mosaic pattern, meaning only certain parts of the body are affected.
The impact of PTEN extends to neurological disorders, with an emerging understanding of its involvement in conditions like autism spectrum disorder (ASD). PTEN mutations have been identified in a subset of individuals with ASD, particularly those with macrocephaly. This highlights PTEN’s broad influence on human development and health, affecting not only cell proliferation but also neural development and function.