TY - JOUR
T1 - Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas
AU - Lallemand, D.
AU - Manent, J.
AU - Couvelard, A.
AU - Watilliaux, A.
AU - Siena, M.
AU - Chareyre, F.
AU - Lampin, A.
AU - Niwa-Kawakita, M.
AU - Kalamarides, M.
AU - Giovannini, M.
PY - 2009/2/12
Y1 - 2009/2/12
N2 - The NF2 gene product, merlin/schwannomin, is a cytoskeleton organizer with unique growth-inhibiting activity in specific cell types. A narrow spectrum of tumors is associated with NF2 deficiency, mainly schwannomas and meningiomas, suggesting cell-specific mechanisms of growth control. We have investigated merlin function in mouse Schwann cells (SCs). We found that merlin regulates contact inhibition of proliferation by limiting the delivery of several growth factor receptors at the plasma membrane of primary SCs. Notably, upon cell-to-cell contact, merlin downregulates the membrane levels of ErbB2 and ErbB3, thus inhibiting the activity of the downstream mitogenic signaling pathways protein kinase B and mitogen-activated protein kinase. Consequently, loss of merlin activity is associated with elevated levels of ErbB receptors in primary SCs. We also observed accumulation of growth factor receptors such as ErbB2 and 3, insulin-like growth factor 1 receptor and platelet-derived growth factor receptor in peripheral nerves of Nf2-mutant mice and in human NF2 schwannomas, suggesting that this mechanism could play an important role in tumorigenesis.
AB - The NF2 gene product, merlin/schwannomin, is a cytoskeleton organizer with unique growth-inhibiting activity in specific cell types. A narrow spectrum of tumors is associated with NF2 deficiency, mainly schwannomas and meningiomas, suggesting cell-specific mechanisms of growth control. We have investigated merlin function in mouse Schwann cells (SCs). We found that merlin regulates contact inhibition of proliferation by limiting the delivery of several growth factor receptors at the plasma membrane of primary SCs. Notably, upon cell-to-cell contact, merlin downregulates the membrane levels of ErbB2 and ErbB3, thus inhibiting the activity of the downstream mitogenic signaling pathways protein kinase B and mitogen-activated protein kinase. Consequently, loss of merlin activity is associated with elevated levels of ErbB receptors in primary SCs. We also observed accumulation of growth factor receptors such as ErbB2 and 3, insulin-like growth factor 1 receptor and platelet-derived growth factor receptor in peripheral nerves of Nf2-mutant mice and in human NF2 schwannomas, suggesting that this mechanism could play an important role in tumorigenesis.
KW - Growth factor receptors
KW - Neurofibromatosis type 2
KW - Proliferation
KW - Schwann cells
KW - Schwannoma
KW - Trafficking
UR - http://www.scopus.com/inward/record.url?scp=60149106862&partnerID=8YFLogxK
U2 - 10.1038/onc.2008.427
DO - 10.1038/onc.2008.427
M3 - Article
C2 - 19029950
AN - SCOPUS:60149106862
SN - 0950-9232
VL - 28
SP - 854
EP - 865
JO - Oncogene
JF - Oncogene
IS - 6
ER -