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Fig. 1. Inducible negative regulators of EGFR signaling. Activation of the EGF
receptor elicits the transcription of negative regulators, such as Argos,
Kekkon and Sprouty, that restrict the range of signaling. EGFR activation
usually leads to Argos and Kekkon induction, and in some settings also to the
induction of Sprouty. Sprouty is also induced by, and inhibits, other
signaling pathways, such as the FGF pathway. The cell expressing Rhomboid
(RHO) and releasing cleaved Spitz (cSPI) is colored orange, the cell where
prominent EGFR activation takes place is green, and the cell where EGFR
activation is repressed is red. (A) Argos is induced only in the cells
receiving the highest levels of the EGFR signal cSPI, i.e. those closest to
the source of ligand processing. Argos is secreted from the cells where it is
produced and associates with cSPI, thus restricting the levels of cSPI
molecules that diffuse beyond the expression domain of Argos. Because Argos
associates with cSPI, the actual range of Argos diffusion is not crucial for
its long-range inhibitory effect. (B) Sprouty is induced in the cells
receiving high and intermediate levels of EGFR activation. Following its
production, Sprouty undergoes tyrosine phosphorylation, which is induced by
the activated receptor, to produce a potent inhibitor. (C) Kekkon is induced
in the cells receiving high and intermediate levels of EGFR activation. The
protein localizes to the plasma membrane, where it forms heterodimers with
EGFR.
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