Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1.
The Nf2 tumor suppressor gene codes for merlin, a protein whose function has been elusive. We describe a novel interaction between merlin and p21-activated kinase 1 (Pak1), which is dynamic and facilitated upon increased cellular confluence. Merlin inhibits the activation of Pak1, as the loss of merlin expression results in the inappropriate activation of Pak1 under conditions associated with low basal activity. Conversely, the overexpression of merlin in cells that display a high basal activity of Pak1 resulted in the inhibition of Pak1 activation. This inhibitory function of merlin is mediated through its binding to the Pak1 PBD and by inhibiting Pak1 recruitment to focal adhesions. This link provides a possible mechanism for the effect of loss of merlin expression in tumorigenesis.
Kissil
Joseph L
JL
Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Wilker
Erik W
EW
Johnson
Kristen C
KC
Eckman
Matthew S
MS
Yaffe
Michael B
MB
Jacks
Tyler
T
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism; D022001:Focal Adhesions / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D016515:Genes, Neurofibromatosis 2 / Q000502:physiology*; D006801:Humans; D051379:Mice; D016518:Neurofibromatosis 2 / Q000201:enzymology / Q000235:genetics*; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D003598:Cytoskeletal Proteins; D025581:Neurofibromin 2; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; C496062:Pxn protein, mouse; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins