An SCF-like ubiquitin ligase complex that controls presynaptic differentiation

Abstract

During synapse formation, specialized subcellular structures develop at synaptic junctions in a tightly regulated fashion. Cross-signalling initiated by ephrins, Wnts and transforming growth factor-beta family members between presynaptic and postsynaptic termini are proposed to govern synapse formation. It is not well understood how multiple signals are integrated and regulated by developing synaptic termini to control synaptic differentiation. Here we report the identification of FSN-1, a novel F-box protein that is required in presynaptic neurons for the restriction and/or maturation of synapses in Caenorhabditis elegans. Many F-box proteins are target recognition subunits of SCF (Skp, Cullin, F-box) ubiquitin-ligase complexes. fsn-1 functions in the same pathway as rpm-1, a gene encoding a large protein with RING finger domains. FSN-1 physically associates with RPM-1 and the C. elegans homologues of SKP1 and Cullin to form a new type of SCF complex at presynaptic periactive zones. We provide evidence that T10H9.2, which encodes the C. elegans receptor tyrosine kinase ALK (anaplastic lymphoma kinase), may be a target or a downstream effector through which FSN-1 stabilizes synapse formation. This neuron-specific, SCF-like complex therefore provides a localized signal to attenuate presynaptic differentiation.

Modulation of the assay system for the sensory integration of 2 sensory stimuli that inhibit each other in nematode Caenorhabditis elegans

“…In C. elegans, FSN-1 is required for the restriction and/or maturation of synapses in presynaptic neurons, and SCD-2 may serve as a downstream target for FSN-1 to stabilize the synaptic formation [43] . The amount and localization of SCD-2 are negatively regulated by FSN-1, and mutation of scd-2 suppresses the synaptic defects of fsn-1 [43] . Interestingly, we found that the sensory integration defects of fsn-1 mutants were obviously inhibited by scd-2 mutation.…”

“…7B, C). It has been indicated that fsn-1 mutants have a slightly reduced body length and normal locomotion [43] . Here it was further demonstrated that both fsn-1 and scd-2 mutants showed a normal phenotype of locomotion behavior as revealed by body bend (Fig.…”

UNC-64 and RIC-4, the plasma membrane-associated SNAREs syntaxin and SNAP-25, regulate fat storage in nematode Caenorhabditis elegans

“…And this neuron-specific, SCF-like complex provides a localized signal to attenuate presynaptic differentiation [22] . Suppressor of Constitutive Dauer formation (SCD-2) may be a target or a downstream effector by which FSN-1 stabilizes synaptic formation [22] .…”

“…Suppressor of Constitutive Dauer formation (SCD-2) may be a target or a downstream effector by which FSN-1 stabilizes synaptic formation [22] . Furthermore, RPM-1 negatively regulates a p38 MAP kinase pathway composed of the dual leucine zipper-bearing MAPKKK DLK-1, the MAPKK MKK-4, and the p38 MAP kinase PMK-3 [23] .…”

Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival

“…[1][2][3][4][5][6] Previous studies have shown that in contrast to other F-box proteins that assemble SCF ubiquitin ligase complexes, Fbxo45 forms an atypical ubiquitin ligase complex that contains Skp1 and the Ring-finger protein PAM (protein-associated with myc) also known as MYCBP2 (mycbinding protein 2). 7,8 Fbxo45 has been linked to the proteasomal degradation of a few targets including p73 9 and Munc13-1. 10 Fbxo45 is one of only six F-box proteins that are conserved in metazoans and the only F-box protein known to contain a SPRY domain, 3 which was first identified as a sequence repeat in the dual-specificity kinase splA and ryanodine receptors.…”