Cell division, the process by which a single cell divides to create two identical daughter cells, is fundamental to life. This process, known as mitosis, is necessary for tissue growth, the replacement of damaged cells, and the repair of injuries. Cell division is tightly controlled by external signals that instruct a cell when to begin and when to stop dividing. These instructions are delivered by specialized protein molecules that act as messengers, ensuring that cell proliferation happens only when and where it is needed.
Growth Factors and Mitogens: The Key Stimulators
The primary protein messengers that stimulate cell division are growth factors and mitogens. A growth factor is a secreted protein that promotes cell growth, increasing the cell’s overall mass. A mitogen specifically triggers the cell to enter mitosis, or cell division. Many signaling molecules function as both, stimulating both cell size and division simultaneously.
Examples include Epidermal Growth Factor (EGF), which aids skin cell formation during wound healing, and Platelet-Derived Growth Factor (PDGF), important for tissue repair. Fibroblast Growth Factor (FGF) and Vascular Endothelial Growth Factor (VEGF) also promote the growth and division of cells in connective tissue and blood vessels, respectively.
Triggering the Cell Cycle: Signaling Pathways
When a stimulatory protein binds to a specific receptor embedded in the cell membrane, it initiates the process. Many of these receptors are Receptor Tyrosine Kinases (RTKs), which become chemically active upon binding. This activation causes the receptor to change shape and start a cascade of events inside the cell.
This cascade is a form of signal transduction, where the external message is relayed through a series of proteins within the cytoplasm. One of the most studied internal pathways is the Ras/MAPK pathway (Mitogen-Activated Protein Kinase). Here, receptor activation leads to the activation of the Ras protein, which then activates a sequence of protein kinases, such as Raf, MEK, and Erk.
Protein kinases are enzymes that activate or inactivate other proteins by adding a phosphate group to them. The final activated kinase in the sequence, Erk, enters the cell nucleus to modify transcription factors. This action promotes the expression of genes that produce proteins necessary to move the cell cycle forward, such as Cyclin D.
The ultimate target is the Restriction Point, also known as the G1 checkpoint, which marks the cell’s commitment to division. Before this point, the cell can pause or return to a resting state, but passing it locks the cell into completing the division process. The resulting Cyclin D proteins partner with other enzymes to inactivate the inhibitory Retinoblastoma protein (Rb), lifting the brakes on the cell cycle and allowing progression toward DNA replication.
Uncontrolled Division and Disease
Precise regulation of these stimulatory proteins is necessary because malfunction can lead to uncontrolled cell proliferation. The genes encoding these normal growth-promoting proteins and their receptors are called proto-oncogenes.
If a proto-oncogene acquires a mutation, it becomes an oncogene, a gene that causes cancer. Malfunctions often involve a receptor becoming constantly “on,” sending continuous division signals without a growth factor. Similarly, mutations in downstream proteins, like the RAS family, can lock them into an active state, causing relentless division, such as the KRAS mutation seen in over 90% of pancreatic cancers.
This continuous, unregulated stimulation bypasses the body’s natural control mechanisms, leading to the growth characteristic of tumors. Understanding the specific proteins and pathways involved provides targets for cancer treatment. Therapies such as Tyrosine Kinase Inhibitors (TKIs) are designed to block the activity of hyperactive receptors, effectively cutting the power to the uncontrolled division signal.