Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling.
Activating mutations in genes of the Ras-mitogen-activated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers; however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo; however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers.
Dow
L E
LE
Research Division, Cell Cycle and Cancer Genetics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Elsum
I A
IA
King
C L
CL
Kinross
K M
KM
Richardson
H E
HE
Humbert
P O
PO
D000818:Animals; D030801:Animals, Genetically Modified; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004330:Drosophila / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D019656:Loss of Heterozygosity / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000235:genetics* / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
D008565:Membrane Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins