WAVE proteins are a family of molecules within cells that orchestrate dynamic changes to a cell’s internal framework, helping manage its shape and movement.
What are WAVE Proteins?
WAVE proteins are a family of three distinct proteins: WAVE1, WAVE2, and WAVE3. These proteins do not function alone but operate as part of a larger assembly called the WAVE regulatory complex (WRC). This complex consists of five proteins: a WAVE protein, Abi, Nap1, Sra1, and HSPC300.
In their inactive state, WAVE proteins are autoinhibited within the WRC in the cell’s fluid interior. For activation, they are recruited to the cell’s outer membrane, where signals like GTPases (e.g., Rac1) and certain phospholipids trigger their activity. This activation involves conformational changes that expose a region of the WAVE protein known as the WCA domain.
How WAVE Proteins Shape Cells
WAVE proteins are central to regulating the actin cytoskeleton, a network of protein filaments that provides structural support and enables cell movement. They achieve this by activating the Arp2/3 complex, a seven-subunit protein complex found in most eukaryotic cells that regulates the actin cytoskeleton.
Upon activation, the Arp2/3 complex initiates the formation of new actin filaments, creating a branched network. This process, called actin polymerization, pushes against the cell membrane, leading to the formation of sheet-like protrusions known as lamellipodia. Lamellipodia are thin, dynamic extensions at the leading edge of migrating cells, allowing them to move and change shape.
This coordinated activity of WAVE proteins, the WRC, and the Arp2/3 complex is fundamental for many cellular processes, including cell migration and the formation of lamellipodia. This mechanism is also involved in processes like embryonic development, immune cell trafficking, and wound healing, where cells need to move and reorganize their structure.
WAVE Proteins and Disease
Dysregulation of WAVE protein activity has implications in various diseases, including cancer and neurological disorders. In cancer, altered WAVE protein function can contribute to disease progression, particularly in metastasis. For instance, elevated expression of WASP/WAVE proteins is observed in invasive breast cancer cells, promoting cell motility and invasion.
WAVE proteins facilitate the formation of actin-dense structures such as invadopodia, which help cancer cells degrade the extracellular matrix and spread. WAVE2 is important for lamellipodia formation, and its deficiency can impair cell motility. Studies have linked WAVE2 to the invasive and metastatic phenotypes in melanoma and colorectal cancer.
In neurological disorders, mutations in WAVE genes and other components of the WAVE complex have been identified in patients with developmental disorders. These conditions include intellectual disability, epileptic seizures, schizophrenia, and autism spectrum disorder. Alterations in the WAVE complex are also implicated in the pathophysiology of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Proper regulation of WAVE proteins is important for maintaining cellular health and preventing disease.