NF2: A Tumor Suppressor

NF2 encodes Merlin/Schwannomin, a protein that regulates cell growth and

proliferation

NF2: A Tumor Suppressor

Mutations in NF2 can cause Neurofibromatosis Type II, a cancer

affecting the auditory nerve and other central nervous system tissues.

NF2 is located on chromosome 22

www.genome.ou.edu

bioweb.wku.edu

Like Rb, NF2 is a Tumor Suppressor

Gutmann and Giovannini

NF2’s protein product, merlin, serves to limit cell proliferation in

several ways:

1. It regulates cytoskeletal anchorage to neighboring cells and the cell matrix.

NF2’s protein product, merlin, serves to limit cell proliferation in

several ways:

1. It regulates cytoskeletal anchorage to neighboring cells and the cell matrix.

2. It blocks the ras pathway.

NF2’s protein product, merlin, serves to limit cell proliferation in

several ways:

1. It regulates cytoskeletal anchorage to neighboring cells and the cell matrix.

2. It blocks the ras pathway.

3. It inhibits cyclin D and progression of the cell cycle.

How does merlin interact with the cytoskeleton?

How does merlin interact with the cytoskeleton?

To answer that, we need to meet a few of its relatives…

Merlin is related to the ERM proteins• The ERM (Ezrin, Radixin, Moesin) family is a group of

membrane and cytoskeleton associated proteins.

McClatchey, A.I., et.al.

Merlin and the ERMs are fairly similar in sequence. They share a FERM domain that allows them to

localize to the plasma membrane.

Gutmann and Giovannini

Merlin is related to the ERM proteins• RHOA belongs to a family of GTPases whose activation

induces phosphorylation/activation of the ERM proteins

McClatchey et.al.

•RAC1 is another member of the RHO-GTPase family, but its activation leads to the

phosphorylation/inactivation of merlin.

McClatchey, A.I.

OnOff

Merlin is related to the ERM proteins

Mutant NF2 allows cell over-proliferation and possibly cell motility by de-polarizing cells and releasing cell-cell and cell-matrix junctions

McClatchey, A.I.

Loss of Merlin

Normal function of ERM Proteins

Remember that Adherens junctions glue cells together and also connect their actin cytoskeletons.

Plasma membrane

Intracellular

Extracellular

DE-cadherin

Armadillo-catenin

F-actinIntracellular

Plasma membrane

Merlin

Plasma membrane

Intracellular

Extracellular

DE-cadherin

Armadillo-catenin

F-actinIntracellular

Plasma membrane

In addition to regulating actin polymerization, merlin and other proteins stabilize adherens junctions.

Merlin

Cells that are mutant in both copies of NF2 do not form functional cell-cell or cell-matrix

junctions…

Lallemand, D., et.al.

Bright green is ß-catenin

In normal cells, Merlin also blocks the Ras pathway.

Alfthan, K., et. al.

Merlin

What is the normal biological role of merlin?

That mouse is a knockout!

What happens when you knock out NF2?

Gutmann and Giovannini

What happens when you knock out NF2?

Gutmann and Giovannini

XNo Gastrulation

What happens when you knock out NF2?

Gutmann and Giovannini/McClatchey

XNo Gastrulation

DEAD

What role does merlin play in causing cancer?

Neurofibromatosis Type II

• The gene NF2 gets its name from the type of cancer it causes: Neurofibromatosis Type II

Neurofibromatosis Type II

• NF2 can be inherited or spontaneous.

R. Weinberg, Cancer Biology

Neurofibromatosis Type II

• The penetrance of NF2 is over 95%

Zucman-Rossi, J., et.al.R. Weinberg, Cancer Biology

Neurofibromatosis Type II:A cancer occurring in about 1/40,000 people

Baser, M.E., et.al.

DNA screens can identify patients who have no symptoms

NF2 mutations in tumor cells are usually deletions; the mutant gene will be smaller than wild type.

Warren, C., et.al.www.stanford.edu

Schwann cells insulate neurons.

www.octc.kctcs.edu

Schwann cells are a type of glial cell.

medinfo.ufl.edu

Vestibular Schwannomas (Acoustic Neuromas) are

unequivocal indicators of NF2

www.nfinc.org

These tumors often lead to deafness.

Benign, but still problematic

http://www.neuroendoscopy.info/brain_tumors.htmwww.patients-baha.com

A Schwannoma:

cclcm.ccf.org

Works Cited:McClatchey, A.I., et.al. “The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation”. Genes and Development. 10. (1997): 1253-65.

Gutmann, D.H., and Giovannini, M. “Mouse Models of Neurofibromatosis 1 and 2”. Neoplasia. 4(2002): 279-90.

Zucman-Rossi, J., et.al. “Exhaustive characterization of the NF2 gene in neurofibromatosis type 2 patients”. Human Molecular Genetics. 7 (1998): 2095-2101.

Baser, M.E., et.al. “Predictors of the Risk of Mortality in Neurofibromatosis Type II”. American Journal of Human Genetics. 71 (2002): 715-723

McClatchey, A.I., “Merlin and ERM Proteins: Unappreciated Roles in Cancer Development?”. Nature Reviews, Cancer. 3 (2003): 877-84.

Lallemand, D., et.al., “NF2 Deficiency Promotes Tumorigenesis and Metastasis by Destabilizing Adherens Junctions”. Genes and Development. 17 (2003): 1090-1100.

Warren, C., et.al., “Identification of Recurrent Regions of Chromosome Loss and Gain in Vestibular Schwannomas Using Comparative Genomic Hybridization”. Journal of Medical Genetics. 40 (2003): 802-6.