Merlin/NF-2 Contact Inhibition of Growth and Tumor Suppression

The cadherins mediate cell-to-cell adhesion through homophilic binding and their engagement results in growth arrest. Cancer cells are refractory to this contact inhibition of growth. We are using biochemistry and optical imaging to examine the signaling mechanisms underlying contact inhibition.

Tomoyo Okada has observed that activation of PAK is sufficient to release normal endothelial cells from contact inhibition. She has discovered that PAK rescues endothelial cells from contact inhibition by phosphorylating and, hence, inactivating the tumor suppressor Merlin. Biochemical and imaging studies indicate that de-phosphorylated Merlin mediates contact inhibition of growth by suppressing Rac signaling.

Model of Merlin's function in contact inhibition of growth.

Merlin is an ERM (Ezrin, Radixin, Moesin) protein, and it is encoded by the NF-2 tumor suppressor gene. This gene is inactivated in Familiar Type II Neurofibromatosis as well as in sporadic Schwannomas, meningiomas, and mesotheliomas. Mouse genetics studies indicate that Merlin may have a broader role in tumor invasion and metastasis than manifested from its specific inactivation in Schwann and mesothelial cells. The biochemical functions of Merlin and the mechanism by which its loss contributes to tumorigenesis are not known. We suspect that inhibition of Rac is only one of multiple functions of Merlin. To understand how Merlin inhibits cell proliferation, we are using the Tandem Affinity Purification (TAP) system and the yeast two-hybrid system to isolate proteins interacting with Merlin and RNA interference to examine their function.