Release of MICAL autoinhibition by semaphorin-plexin signaling promotes interaction with collapsin response mediator protein.

Semaphorin activation of Plexin (Plex) receptors provides axonal guidance during neuronal development. Two families of cytoplasmic proteins, collapsin response mediator proteins (CRMPs) and molecules interacting with CasL (MICALs), have been implicated in Plexin function. The relationship between CRMP and MICAL signaling has not been defined nor is the mechanism by which Plexin activates MICAL clear. Here, we show that CRMP and MICAL physically associate and that Sema signaling promotes this association. MICAL enzymatic activity is inhibited by the C-terminal domain of MICAL. CRMP and Plexin associate with nonenzymatic and enzymatic domains of MICAL and together release MICAL enzymatic autoinhibition. In addition to acting as an upstream MICAL activator, CRMP functions downstream of MICAL, inhibiting the catalytic domain. A constitutively active CRMP mutant inhibits MICAL activity more potently than does wild-type CRMP, suggesting that CRMP or a CRMP-associated factor is a MICAL substrate. Thus, complex Plex/CRMP/MICAL interactions transduce Semaphorin signaling into axon guidance.