POSH is an Intracellular Signal Transducer for the Axon Outgrowth Inhibitor Nogo66

Abstract

Myelin-derived inhibitors limit axon outgrowth and plasticity during development and in the adult mammalian CNS. Nogo66, a functional domain of the myelin-derived inhibitor NogoA, signals through the PirB receptor to inhibit axon outgrowth. The signaling pathway mobilized by Nogo66 engagement of PirB is not well understood. We identify a critical role for the scaffold protein Plenty of SH3s (POSH) in relaying process outgrowth inhibition downstream of Nogo66 and PirB. Blocking the function of POSH, or two POSH-associated proteins, leucine zipper kinase (LZK) and Shroom3, with RNAi in cortical neurons leads to release from myelin and Nogo66 inhibition. We also observed autocrine inhibition of process outgrowth by NogoA, and suppression analysis with the POSH-associated kinase LZK demonstrated that LZK operates downstream of NogoA and PirB in a POSH-dependent manner. In addition, cerebellar granule neurons with an RNAi-mediated knockdown in POSH function were refractory to the inhibitory action of Nogo66, indicating that a POSHdependent mechanism operates to inhibit axon outgrowth in different types of CNS neurons. These studies delineate an intracellular signaling pathway for process outgrowth inhibition by Nogo66, comprised of NogoA, PirB, POSH, LZK, and Shroom3, and implicate the POSH complex as a potential therapeutic target to enhance axon outgrowth and plasticity in the injured CNS.

Activation of LILRB2 signal pathway in temporal lobe epilepsy patients and in a pilocarpine induced epilepsy model

“…Recent studies confirmed that the scaffold proteins of SH3s (POSH), actin-myosin regulatory protein SHROOM3, and Rho Kinase (ROCK) have been involved in the downstream signaling pathways of PirB to participate in the inhibition of neuronal outgrowth (Dickson et al, 2010;Taylor et al, 2008). The important downstream molecules in the PirB pathway were also observed in the present study.…”

Targeted inhibition of the Shroom3–Rho kinase protein–protein interaction circumvents Nogo66 to promote axon outgrowth

“…Therefore, we hypothesized that pharmacological inhibition of the Shroom3/ROCK2 protein–protein interaction with CCG-17444 would relieve neurite outgrowth inhibition, as observed for RNA interference (RNAi) mediated reduction of POSH or Shroom3 function [14, 16]. To test this hypothesis, we examined the effect of compound treatment on neurite outgrowth in differentiated neurons derived from mouse P19 embryonic carcinoma cells [14, 16, 21, 22]. Neurons were generated by transfection with the neural basic helix-loop-helix protein Neurogenin 2 (Ngn2) [16, 21].…”

“…This signaling complex includes the actin-myosin regulator Shroom3, Rho kinase, and leucine zipper kinase (LZK or MAP3K12) [14, 16]. Shroom3 directly binds to Rho kinase [16–19].…”

Surgical Intensive Care Unit Optimal Mobilisation Score (SOMS) trial: a protocol for an international, multicentre, randomised controlled trial focused on goal-directed early mobilisation of surgical ICU patients

“…Specifically, we will focus on polymorphisms in CLOCK,39 NPAS2,40 PER2,41 PER3,42 PDE4D,43 MUC1,44 ATP2B1,44 45 DCDC5,44 TRPM6,44 SHROOM344 46 and MDS144 genes, which are associated with sleepiness, sleep phase and potentially respiratory muscle weakness. If consent is received for the genetic study, blood is drawn and stored prior to transport to the Center for Human Genetic Research at Massachusetts General Hospital where blood samples will be processed and genetic analysis performed.…”