How do inhibitory phosphatases work?

We present a hypothesis regarding the mode of induction of the inhibitory phosphatases SHP-1 and SHIP in hematopoietic cells. One mode is a general one in which the phosphatase regulates but does not abort signal transduction and biology. Regulator phosphatases are induced by directly or indirectly engaging the amino acid motifs present in the activating receptor, and act to control the biochemical and biological output. The other mode of induction is a specific one, which critically involves paired co-clustering of activating and inhibitory receptors. Phosphatases working in this way act only under conditions of paired co-clustering of activating and inhibitory receptors, and directly bind amino acid motifs present in the inhibitory receptor. However, this mode of induction is apparently more efficient, as cellular activation is completely aborted. This review presents several examples of each mode of inhibition and speculates on their mechanisms.