Cellular mechanisms of heterogeneity in NF2-mutant schwannoma.

Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded successful treatment.

Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface.

The architectural and biochemical features of the plasma membrane are governed by its intimate association with the underlying cortical cytoskeleton. The neurofibromatosis type 2 (NF2) tumor suppressor merlin and closely related membrane:cytoskeleton-linking protein ezrin organize the membrane:cytoskeleton interface, a critical cellular compartment that both regulates and is regulated by growth factor receptors. An example of this poorly understood interrelationship is macropinocytosis, an ancient process of nutrient uptake and membrane remodeling that can both be triggered by growth factors and manage receptor availability.

EGFR-induced cytoskeletal changes drive complex cell behaviors: The tip of the iceberg.

Cytoskeletal networks are dramatically reorganized upon EGF stimulation to enable complex cell behaviors such as cell-cell communication, migration and invasion, and cell division. In this issue of , Roth and Pike use proteomic methods to identify several effectors of EGF responses. The findings show the interdependent nature of growth factor signaling and the cytoskeleton and identify potential new therapeutic targets for treating cancer and other growth factor-driven diseases.

Cell-Cell Contact and Receptor Tyrosine Kinase Signaling.

The behavior of cells within tissues is governed by the activities of adhesion receptors that provide spatial cues and transmit forces through intercellular junctions, and by growth-factor receptors, particularly receptor tyrosine kinases (RTKs), that respond to biochemical signals from the environment. Coordination of these two activities is essential for the patterning and polarized migration of cells during morphogenesis and for homeostasis in mature tissues; loss of this coordination is a hallmark of developing cancer and driver of metastatic progression. Although much is known about the individual functions of adhesion and growth factor receptors, we have a surprisingly superficial understanding of the mechanisms by which their activities are coordinated.

NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin.

The proliferation of normal cells is inhibited at confluence, but the molecular basis of this phenomenon, known as contact-dependent inhibition of proliferation, is unclear. We previously identified the neurofibromatosis type 2 (NF2) tumor suppressor Merlin as a critical mediator of contact-dependent inhibition of proliferation and specifically found that Merlin inhibits the internalization of, and signaling from, the epidermal growth factor receptor (EGFR) in response to cell contact. Merlin is closely related to the membrane-cytoskeleton linking proteins Ezrin, Radixin, and Moesin, and localization of Merlin to the cortical cytoskeleton is required for contact-dependent regulation of EGFR.

p120-catenin binding masks an endocytic signal conserved in classical cadherins.

p120-catenin (p120) binds to the cytoplasmic tails of classical cadherins and inhibits cadherin endocytosis. Although p120 regulation of cadherin internalization is thought to be important for adhesive junction dynamics, the mechanism by which p120 modulates cadherin endocytosis is unknown. In this paper, we identify a dual-function motif in classical cadherins consisting of three highly conserved acidic residues that alternately serve as a p120-binding interface and an endocytic signal.